Variant: NM_000314.6(PTEN):c.-975G>C

CA000654

127685 (ClinVar)

Gene: PTEN

Condition: PTEN hamartoma tumor syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: d5ebdbde-0541-439f-8bbb-2234f7aa3636

Approved on: 2019-06-25

Published on: 2019-07-23

HGVS expressions

NM_000314.6:c.-975G>C
NM_000314.6(PTEN):c.-975G>C
NC_000010.11:g.87863494G>C
CM000672.2:g.87863494G>C
NC_000010.10:g.89623251G>C
CM000672.1:g.89623251G>C
NC_000010.9:g.89613231G>C
NG_007466.2:g.5057G>C
NG_033079.1:g.4944C>G
NM_000314.5:c.-975G>C
NM_001304717.2:c.-456G>C
NM_001304718.1:c.-1680G>C
ENST00000371953.7:c.-976G>C
ENST00000610634.1:c.-1078G>C

Likely Benign

• Met criteria codes: BS1 BP5

• Not Met criteria codes: BS3 BS4 PVS1 BS2 BP7 BP4 BP2 PS3 PS4 PS2 PS1 BA1 PP2 PP3 PP1 PM2 PM6 PM4 PM1 PM5

Expert Panel

PTEN VCEP

Criteria Specification Information

Evidence submitted by expert panel

PTEN VCEP

PTEN c.-975G>C (g.89623251G>C) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). BS1: Allele frequency of 0.006 (0.6%, 21/3466 alleles) in the European (Finnish) subpopulation and 0.002 (0.2%, 30/14,976) in the European (Non-Finnish) subpopulation of the gnomAD cohort. (PMID 27535533) BP5: Variant found in multiple cases with alternate molecular basis for disease. (internal laboratory contributors SCV000187238.1, SCV000149489.5)

Met criteria codes

• BS1: Variant is found in 55/30846 control chromosomes at a frequency of 0.0017831. Found in 21/3466 individuals of European/Finnish ancestry and 30/14976 European/non-Finnish ancestry. Allele frequency fall in the range of 0.001 up to 0.01 in a population with > 2000 alleles and variant is present in > 5 alleles. FH: I agree
• BP5: Internal data from GeneDx shows variant in multiple cases with other pathogenic gene mutation. Some information about personal or family history and overlap is unlikely. (1) proband, BRCA1+, no cancer fam hx of breast, uterine ovarian, pancreatic, bile duct, stomach (2) proband: breast ca and MSH6+, fam hx of ovarian, panc, lung (3) proband, no cancer and BRCA1+, fam hx: breast, ovarian, esophageal (4) proband TNBC and BRCA2+, fam hx: breast, prostate (5) proband no cancer but EPCAM/MSH2+, fam hx: colon, endometrial (6) proband had breast and ovarian and BRCA1+, fam hx: prostate and leukemia (7) proband had small bowel ca and MSH6+, fam hx: NA (8) kid with macrocephaly, DD, dysmorphic and NSD1+, negative fam hx (9) proband no cancer and BRCA1+ family hx: breast, prostate, lung (10) proband with colon x 2 and MSH2+ fam hx: colon, ovarian, breast (11) proband with TNBC and MSH6+, fam hx: breast and panc ca. FH (BP5): internal data for observations with a pathogenic variant in a different gene explaining the patient's phenotype: 1. MSH2 mutation. MSH2/MSH6-deficient CRC at 62y. Family hx: mother CRC dx 3X 30s-60s; MGM OV 40s. 2. proband dx with an extra-adrenal paraganglioma @21 SDHB VLP.

Not Met criteria codes

• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: One internal case from Charis Eng's lab: co-occurrence with PTEN mutationn c.407_423del17 p.(Cys136Serfs*38) phase (whether in cis or trans) unknown. Female, age 60, consented age 49; CC score: 14; OFC: Unknown; Breast cancer, dx 33 -Invasive papillary adenocarcinoma, laterality unknown; GI polyps Lower GI Ganglioneuroma (x1); Visceral hemangioma. Family: None.
• PS3: Heikkinen et al (2011) analyzed the affects of promoter variants in PTEN and breast cancer progression and survival. The presence of this variant is associated with poor survival in breast cancer patients. MPerpich entry.
• PS4: 25 internal cases from Charis Eng's lab all with CC scores less than 18 so none meet criteria for PS4, PS4_moderate, PS4_supporting.
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline