Submissions for variant NM_000059.4(BRCA2):c.1820A>C (p.Lys607Thr)

gnomAD frequency: 0.00002  dbSNP: rs55962656

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000043901	SCV000071914	likely benign	Hereditary breast ovarian cancer syndrome	2023-11-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163031	SCV000213519	likely benign	Hereditary cancer-predisposing syndrome	2018-08-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV000859148	SCV000512343	likely benign	not provided	2018-07-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18375895, 21990134, 25348012, 21990165)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000436051	SCV000694572	likely benign	not specified	2018-02-05	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1820A>C (p.Lys607Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3e-05 in 236036 control chromosomes in gnomAD and literature. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (3e-05 vs 7.50E-04), allowing no conclusion about variant significance. c.1820A>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Spurdle_2008) without strong evidence for pathogenicity. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.5563_5563delinsGGATCC, p.Ile1856insGly; BRCA1 c.5503C>T, p.Arg1835X; BRCA2 c.7558C>T, p.Arg2520X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000077269	SCV000785309	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-07-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163031	SCV000911866	likely benign	Hereditary cancer-predisposing syndrome	2018-01-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000859148	SCV001133696	likely benign	not provided	2023-06-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000077269	SCV001139012	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262739	SCV001440717	uncertain significance	Familial cancer of breast	2019-01-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163031	SCV002533269	likely benign	Hereditary cancer-predisposing syndrome	2021-02-13	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000163031	SCV003851669	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)	RCV000077269	SCV000109066	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077269	SCV000145958	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-06-20	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000077269	SCV004228380	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BS1(Supporting)+BP1(Strong)+BP5(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)