Submissions for variant NM_000059.4(BRCA2):c.1814T>C (p.Ile605Thr)

gnomAD frequency: 0.00002  dbSNP: rs80358468

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588653	SCV000210570	likely benign	not provided	2018-12-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000165793	SCV000216539	likely benign	Hereditary cancer-predisposing syndrome	2017-09-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000077667	SCV000488453	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-03-31	criteria provided, single submitter	clinical testing
Invitae	RCV001082118	SCV000635181	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488376	SCV000694571	uncertain significance	not specified	2023-12-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1814T>C (p.Ile605Thr) results in a non-conservative amino acid change in 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 8.3e-06 in 241080 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1814T>C has been reported in the literature in a family affected with breast and/or ovarian cancer without strong evidence of causality (Machackova_2019). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22703879, 31294896, 31112341, 31409081). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=1) or likely benign (n=6). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000165793	SCV001342192	likely benign	Hereditary cancer-predisposing syndrome	2018-11-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588653	SCV001501462	likely benign	not provided	2020-08-01	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165793	SCV003851660	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Sharing Clinical Reports Project (SCRP)	RCV000077667	SCV000109470	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2010-10-06	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077667	SCV000145953	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing