Submissions for variant NM_000059.4(BRCA2):c.5278T>G (p.Ser1760Ala)

gnomAD frequency: 0.00001  dbSNP: rs28897735

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131676	SCV000186712	likely benign	Hereditary cancer-predisposing syndrome	2022-07-18	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	RCV000985542	SCV000516136	likely benign	not provided	2021-03-30	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21990134, 18375895, 24489791, 21990165, 27208206, 31131967)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476848	SCV000549865	likely benign	Hereditary breast ovarian cancer syndrome	2024-11-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131676	SCV000911758	likely benign	Hereditary cancer-predisposing syndrome	2017-08-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000440605	SCV000916887	likely benign	not specified	2021-04-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5278T>G (p.Ser1760Ala) results in a 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 3.2e-05 in 250644 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5278T>G has been reported in the literature in individuals affected with breast cancer (example, Spurdle_2008, Whiley_2014). These report(s) do 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus leaning towards a likely benign outcome (n=4) (VUS, n=1). Based on the emerging consensus among peers supporting a neutral outcome as evidence outlined above, the variant was re-classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985542	SCV001133824	uncertain significance	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131676	SCV002536120	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-07	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131676	SCV003847134	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).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000440605	SCV005090039	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000076927	SCV000108724	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-04-25	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353578	SCV000591957	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	BRCA2, EXON11, c.5278T>G, p.Ser1760Ala, Heterozygous, Uncertain Significance The BRCA2 p.Ser1760Ala variant was identified in 3 of 1548 proband chromosomes (frequency: 0.002) from Australian and British individuals or families with breast or ovarian cancer and was not identified in 360 control chromosomes from healthy individuals (Spurdle 2008, Plaskocinska 2016, Hondow 2011). The variant was identified in dbSNP (ID: rs28897735) as “With other allele”, ClinVar (classified as likely benign by GeneDx, Ambry Genetics and Color; and as uncertain significance by Invitae, SCRP and Integrated Genetics/Laboratory Corporation of America), and LOVD 3.0. The variant was not identified in UMD-LSDB. The variant was identified in control databases in 8 of 245312 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Other in 1 of 5466 chromosomes (freq: 0.0002) and European Non-Finnish in 7 of 111174 chromosomes (freq: 0.00006), but not in the African, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Ser1760 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the Ala variant to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. Assessment Date: 2019/07/11. References (PMIDs): 18375895, 21990165, 27208206, 21702907, 21990134
BRCAlab, Lund University	RCV000076927	SCV004243663	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing