Submissions for variant NM_000059.4(BRCA2):c.4436G>C (p.Ser1479Thr)

gnomAD frequency: 0.00001  dbSNP: rs80358678

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001081171	SCV000072427	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131309	SCV000186281	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-09	criteria provided, single submitter	clinical testing	The p.S1479T variant (also known as c.4436G>C), located in coding exon 10 of the BRCA2 gene, results from a G to C substitution at nucleotide position 4436. The serine at codon 1479 is replaced by threonine, an amino acid with similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer (Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Harismendy O et al. Breast Cancer Res, 2013 Dec;15:R115). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000044414	SCV000210335	likely benign	not specified	2018-01-16	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl	RCV000113303	SCV000489434	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044414	SCV000694773	uncertain significance	not specified	2022-07-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4436G>C (p.Ser1479Thr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249702 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4436G>C has been reported in the literature in individuals affected with breast and ovarian cancers without strong evidence for causality (e.g.Borg_2010, Mattocks_2010, Harismendy_2013, Delahunty_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported in the BIC database (BRCA2 c.3911_3911delC, p.Thr1304Ilefs; BRCA1 c.3710_3710delT, p.Ile1237Asnfs), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function using a mouse embryonic stem cell-based assay (e.g.Biswas_2020). The variant was able to rescue the lethal phenotype as effectively as wild-type BRCA2, suggesting this variant has little to no damaging effect on protein function. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=3) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Color Diagnostics, LLC DBA Color Health	RCV000131309	SCV000903291	likely benign	Hereditary cancer-predisposing syndrome	2017-06-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586286	SCV001133796	likely benign	not provided	2022-12-07	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131309	SCV003850507	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).
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113303	SCV000146422	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000113303	SCV000223758	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-30	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000586286	SCV001553041	uncertain significance	not provided		no assertion criteria provided	clinical testing