Submissions for variant NM_000059.4(BRCA2):c.825A>T (p.Lys275Asn)

gnomAD frequency: 0.00001  dbSNP: rs397507399

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131188	SCV000186137	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	clinical testing	The p.K275N variant (also known as c.825A>T), located in coding exon 9 of the BRCA2 gene, results from an A to T substitution at nucleotide position 825. The lysine at codon 275 is replaced by asparagine, an amino acid with similar properties. One study reported this alteration as being identified in 1/240 HBOC patients (Schenkel LC et al. J Mol Diagn, 2016 09;18:657-667). In addition, another study reported this variant in 1/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is poorly 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	RCV001283942	SCV000210255	uncertain significance	not provided	2022-08-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 1053A>T; This variant is associated with the following publications: (PMID: 31409081, 27376475, 33471991)
Invitae	RCV000257932	SCV000635648	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131188	SCV000903079	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-14	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 275 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 1/60463 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_002328) and in an individual affected with breast or ovarian cancer (PMID: 27376475). This variant also has been reported in 1 individual age 70 years or older without cancer in the FLOSSIES database. This variant has been identified in 2/244196 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001283942	SCV001469458	uncertain significance	not provided	2020-08-31	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001283942	SCV001715037	uncertain significance	not provided	2019-11-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797593	SCV002041738	uncertain significance	not specified	2021-11-05	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.825A>T (p.Lys275Asn) 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 8.2e-06 in 244196 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.825A>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer and in unaffected controls (example, Machackova_2019, Schenkel_2016, Dorling_2021), however these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) has been reported in the UMD database (BRCA1 c.308insTTTA, p.Asn103IlefsX2), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; five have reported this variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131188	SCV003848058	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)	RCV000031730	SCV000054337	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing