Variant: NM_024675.3(PALB2):c.3350+4A>G

CA269618

126737 (ClinVar)

Gene: PALB2

Condition: hereditary breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: 5d950d2e-2b79-4881-98cf-c7e7b0ae3a3e

HGVS expressions

NM_024675.3:c.3350+4A>G
NM_024675.3(PALB2):c.3350+4A>G
NC_000016.10:g.23607860T>C
CM000678.2:g.23607860T>C
NC_000016.9:g.23619181T>C
CM000678.1:g.23619181T>C
NC_000016.8:g.23526682T>C
NG_007406.1:g.38498A>G
ENST00000261584.9:c.3350+4A>G
ENST00000261584.8:c.3350+4A>G
ENST00000566069.5:n.117-4191A>G
ENST00000568219.5:c.2465+4A>G
NM_024675.4:c.3350+4A>G
NM_024675.4(PALB2):c.3350+4A>G

Likely Pathogenic

• Met criteria codes: PM3 PVS1

• Not Met criteria codes: PP3 PM2 BA1 BS1 BP4 PS1

Expert Panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

Criteria Specification Information

Criteria Specification: ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PALB2 Version 1.0.0

Evidence submitted by expert panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

The c.3350+4A>G variant in PALB2 is an intronic variant proximal to the exon 12 canonical splice donor site. This variant has a minor allele frequency in gnomAD v2.1.1 of 0.000008796 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). This intronic variant is proximal to the exon 12 canonical splice donor site. RNA analysis demonstrated that the variant impacts splicing, generating two abnormal products: r.3202_ 3350del149, in which exon 12 is skipped, and r.3350insGCAG, which utilizes a cryptic splice donor site, both of which result in translational frameshifts. The resulting mRNA products are not expected to be susceptible to nonsense-mediated decay, but impacts the WD40 domain, which is a functionally important region (PMID: 17200671, additional information in Reinhard Kalb dissertation (urn:nbn:de:bvb:20-opus-25823)). This variant has been detected in an individual with Fanconi Anemia that is compound heterozygous for this variant and a pathogenic variant confirmed in trans by parental testing (PALB2 c.2393_2394insCT (p.Thr799fs), PMID: 17200671). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PVS1(RNA), PM3)

Met criteria codes

• PM3: This variant has been detected in two individuals with Fanconi Anemia. One individual was compound heterozygous for the variant and a pathogenic variant confirmed in trans by parental testing (PALB2 c.2393_2394insCT (p.Thr799fs), 2 points, PMID: 17200671). One individual was homozygous for the variant (0 points (not scored due to lack of confirmatory phenotypic and chromosome breakage test information, Invitae) (PM3).
• PVS1: RNA analysis demonstrated that the variant impacts splicing, generating two abnormal products: r.3202_ 3350del149, in which exon 12 is skipped, and r.3350insGCAG, which utilizes a cryptic splice donor site, both of which result in translational frameshifts. Leakiness was not ascertained. The resulting mRNA products are not expected to be susceptible to nonsense-mediated decay, but the WD40 domain would be altered in the proteins produced (PMID: 17200671, additional information in Reinhard Kalb dissertation (urn:nbn:de:bvb:20-opus-25823), PVS1_O).

Not Met criteria codes

• PP3: The results from three in silico predictors (SpliceAI AL: 0.00/DL: 0.14/AG: 0.00/DG: 0.01; MaxEntScan wild type: 3.10, variant: 2.53 (-18.4% change); NNSplice wild type: no splice site predicted, variant: new GT donor site predicted at c.3350+5 and c.3350+6 (score 0.66)) do not agree, providing no evidence that correlates with a damaging or benign impact on PALB2 function. Additionally, PP3 for splice predictions may not be applied in addition to PVS1_O. Note that splice analysis may be complicated by the noncanonical wild type exon 12 splice donor (GC) (PMID: 30233647).
• PM2: The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008796 (1/113694 alleles) in non-Finnish European population. PM2_Supporting, BS1, and BA1 are not met.
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: 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
• PS1: A different nucleotide change at this position has been observed (c.3350+4A>C), but has not yet been classified by the HBOP VCEP.

Approved on: 2023-04-05

Published on: 2023-04-07