Submissions for variant NM_000059.4(BRCA2):c.6225A>C (p.Lys2075Asn)

dbSNP: rs80358863

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130739	SCV000185630	likely benign	Hereditary cancer-predisposing syndrome	2017-11-13	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	RCV000255403	SCV000321473	uncertain significance	not provided	2020-03-03	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 6453A>C; This variant is associated with the following publications: (PMID: 31131967)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000558324	SCV000635498	likely benign	Hereditary breast ovarian cancer syndrome	2024-11-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130739	SCV000683761	likely benign	Hereditary cancer-predisposing syndrome	2022-08-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000076957	SCV000785313	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-07-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194389	SCV001363897	likely benign	not specified	2025-01-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6225A>C (p.Lys2075Asn) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249130 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6225A>C has been reported in the literature as a VUS in settings of multigene panel testing among individuals affected with Phyllodes tumors (PT), that are rare fibroepithelial breast neoplasms (Rosenberger_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Ikegami_2020). These results showed no damaging effect of this variant on homology directed repair (HDR capacity) based on a high throughput cell based viability assay (MANO-B method) to evaluate drug sensitivity of the BRCA2 variants treated with PARP inhibitors (olaparib, niraparib, rucaparib and carboplatin) at various concentrations. The following publications have been ascertained in the context of this evaluation (PMID: 32444794, 32504368). ClinVar contains an entry for this variant (Variation ID: 91440). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255403	SCV001469703	uncertain significance	not provided	2024-02-21	criteria provided, single submitter	clinical testing	The BRCA2 c.6225A>C (p.Lys2075Asn) variant has been reported in the published literature in an individual with a phyllodes tumor of the breast (PMID: 32504368 (2020)) and in an elderly cancer free woman (FLOSSIES (https://whi.color.com/)). In addition, this variant displays neutral PARP inhibitor sensitivity in a high throughput cell viability assay (MANO-B) (PMID: 32444794 (2020)). This variant has also been reported to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Centogene AG - the Rare Disease Company	RCV000076957	SCV002059858	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-11-23	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130739	SCV003852334	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)	RCV000076957	SCV000108754	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-06-13	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000076957	SCV000146800	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing