Submissions for variant NM_000059.4(BRCA2):c.4094G>A (p.Cys1365Tyr)

gnomAD frequency: 0.00004  dbSNP: rs80358657

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031459	SCV000244446	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000136
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044346	SCV000072359	benign	Hereditary breast ovarian cancer syndrome	2024-01-05	criteria provided, single submitter	clinical testing
GeneDx	RCV001535398	SCV000210602	likely benign	not provided	2021-03-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32659497, 29958926, 29309945, 28767289, 25479140, 27997549, 23633455, 22711857, 27376475, 21990134, 17924331, 19491284, 10923033, 24323938)
Ambry Genetics	RCV000162841	SCV000213328	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl	RCV000031459	SCV000784931	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-02-14	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770725	SCV000902204	uncertain significance	Breast and/or ovarian cancer	2016-07-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162841	SCV000910846	benign	Hereditary cancer-predisposing syndrome	2015-12-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160222	SCV000919002	likely benign	not specified	2022-12-05	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4094G>A (p.Cys1365Tyr) results in a non-conservative amino acid change located in the BRCA2 repeat region, between the repeats BRC2 and BRC3 (IPR002093) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249264 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.4094G>A, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer or other tumor phenotypes, however these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with other pathogenic variants have been reported (with BRCA1 c.1175_1214del, p.Leu392_Ser405fs in the BIC database), providing supporting evidence for a benign role. The variant was predicted to be neutral based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious mutations (Lindor 2012) and using a model based co-occurrence in trans with a deleterious mutation, personal and family history of cancer, and analysis of co-segregation with disease (Easton 2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters including an expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as enign/likely benign (n=6) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000162841	SCV002533848	likely benign	Hereditary cancer-predisposing syndrome	2021-05-06	criteria provided, single submitter	curation
Sharing Clinical Reports Project (SCRP)	RCV000031459	SCV000054064	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2009-06-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031459	SCV000146373	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732564	SCV005345872	likely benign	BRCA2-related disorder	2019-07-19	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).