Variant: NM_004360.5(CDH1):c.1409C>T (p.Thr470Ile)

CA151518

127913 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: 1149db17-78d8-4b2c-bbd4-e5f6b193a1eb

Approved on: 2023-08-10

Published on: 2023-08-10

HGVS expressions

NM_004360.5:c.1409C>T
NM_004360.5(CDH1):c.1409C>T (p.Thr470Ile)
NC_000016.10:g.68815603C>T
CM000678.2:g.68815603C>T
NC_000016.9:g.68849506C>T
CM000678.1:g.68849506C>T
NC_000016.8:g.67407007C>T
NG_008021.1:g.83312C>T
ENST00000261769.10:c.1409C>T
ENST00000261769.9:c.1409C>T
ENST00000422392.6:c.1226C>T
ENST00000562836.5:n.1480C>T
ENST00000566510.5:c.*75C>T
ENST00000566612.5:c.1409C>T
ENST00000611625.4:c.1472C>T
ENST00000612417.4:c.1409C>T
ENST00000621016.4:c.1409C>T
NM_004360.3:c.1409C>T
NM_001317184.1:c.1226C>T
NM_001317185.1:c.-140C>T
NM_001317186.1:c.-411C>T
NM_004360.4:c.1409C>T
NM_001317184.2:c.1226C>T
NM_001317185.2:c.-140C>T
NM_001317186.2:c.-411C>T

Benign

• Met criteria codes: BP2_Strong BS2

• Not Met criteria codes: PS2 PS4 PS3 PS1 PP4 PP1 PP2 PP3 PM1 PM4 PM5 PM3 PM6 PM2 BA1 PVS1 BS3 BS4 BS1 BP3 BP1 BP4 BP7 BP5

Expert Panel

CDH1 VCEP

Criteria Specification Information

Criteria Specification: ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1

Evidence submitted by expert panel

CDH1 VCEP

The c.1409C>T (p.Thr470Ile) variant was observed in trans with a known pathogenic CDH1 variant with phase confirmed (BP2_Strong; PMID: 9537325). This variant was also observed in the homozygous state in at least 6 individuals without a personal and/or family history of diffuse gastric cancer, signet ring cell tumor or lobular breast cancer (BP2_Strong; internal laboratory contributors). Additionally, this variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BP2_Strong, BS2.

Met criteria codes

• BP2_Strong: PMID:9537325 - Observed in an early onset diffuse gastric cancer family. A pathogenic (c.2382-2386insC) CDH1 variant was also identified and reported to segregate with disease in the family. This variant p.Thr470Ile, is reported NOT to segregate with disease in the family, this suggests that the two variants are in trans. Also, seen in 6 homozygotes.
• BS2: 388 non-HDGC individuals.

Not Met criteria codes

• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: 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
• PP4: 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
• 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
• PM1: 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
• PM5: 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
• PM2: ExAC - 0.003% - 4 total allele count. (East Asian 0.03%). GnomAD 0.004% - 10 total allele count. (East Asian 0.04%).
• BA1: ExAC - 0.003% - 4 total allele count. (East Asian 0.03%). GnomAD 0.004% - 10 total allele count. (East Asian 0.04%).
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: ExAC - 0.003% - 4 total allele count. (East Asian 0.03%). GnomAD 0.004% - 10 total allele count. (East Asian 0.04%).
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: 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
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: Observed in 4 patients with pathogenic variants in other cancer assoc. genes.; concern for overlapping phenotypes