Submissions for variant NM_000059.4(BRCA2):c.8572C>A (p.Gln2858Lys)

dbSNP: rs80359112

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045560	SCV000073573	likely benign	Hereditary breast ovarian cancer syndrome	2024-09-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000766652	SCV000210477	uncertain significance	not provided	2017-04-19	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8572C>A at the cDNA level, p.Gln2858Lys (Q2858K) at the protein level, and results in the change of a Glutamine to a Lysine (CAA>AAA). Using alternate nomenclature, this variant would be defined as BRCA2 8800C>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gln2858Lys was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Gln2858Lys occurs at a position that is conserved in mammals and is located in the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Gln2858Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000166603	SCV000217407	likely benign	Hereditary cancer-predisposing syndrome	2022-01-11	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000766652	SCV000600814	likely benign	not provided	2023-03-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166603	SCV000689135	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with lysine at codon 2858 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 27153395, 33471991; Leiden Open Variation Database DB-ID BRCA2_000348). This variant has been identified in 1/251230 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.
Counsyl	RCV000113961	SCV000785961	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212278	SCV001361804	likely benign	not specified	2024-07-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8572C>A (p.Gln2858Lys) results in a conservative amino acid change located in the Tower domain (IPR015205) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.9e-05 in 1613808 control chromosomes (gnomAD database v4). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (1.9e-05 vs 0.00075), allowing no conclusion about variant significance. c.8572C>A has been reported in the literature as a VUS in at-least one individual affected with Ovarian Cancer and no family history of breast/ovarian cancer in first degree relatives, who underwent analysis limited to BRCA1/2 genes (example, Sokolenko_2020). 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 its impact on protein function have been reported. At-least two co-occurrences with other pathogenic variant(s) have been reported in the UMD database (BRCA2 c.9117G>A, p.Pro3039Pro; BRCA2 c.5909C>A, p.Ser1970*), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function and reports the variant as functional (Biswas_2023). The following publications have been ascertained in the context of this evaluation (PMID: 19043619, 20858050, 22632462, 25348012, 31112341, 32776218, 37922907). ClinVar contains an entry for this variant (Variation ID: 52623). Based on the evidence outlined above, the variant was classified as likely benign.
All of Us Research Program, National Institutes of Health	RCV004803920	SCV004846044	uncertain significance	BRCA2-related cancer predisposition	2024-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with lysine at codon 2858 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Functional studies have shown this variant does not impact BRCA2 function in a homology-directed DNA repair assay (PMID: 35736817), or cell viability and drug sensitivity in mouse embryonic stem cells (PMID: 37922907). This variant has been reported in individuals affected with breast cancer (PMID: 27153395, 33471991; Leiden Open Variation Database DB-ID BRCA2_000348) and in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.102 and 0.1509, respectively (PMID: 31131967). This variant has been identified in 1/251230 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.
Baylor Genetics	RCV004566852	SCV005058347	uncertain significance	Familial cancer of breast	2024-03-26	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113961	SCV000147401	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing