Submissions for variant NM_000059.4(BRCA2):c.5683G>A (p.Glu1895Lys)

gnomAD frequency: 0.00001  dbSNP: rs146351301

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131358	SCV000186334	likely benign	Hereditary cancer-predisposing syndrome	2018-07-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240768	SCV000265934	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Invitae	RCV000227239	SCV000283268	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000590426	SCV000567968	uncertain significance	not provided	2022-12-28	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer (Borg et al., 2010; Wong-Brown et al., 2015; Zhong et al., 2016; Li et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as 5911G>A; This variant is associated with the following publications: (PMID: 25682074, 27257965, 30702160, 20104584, 28664449, 29192238, 31825140, 32467295, 32377563, 31907386)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265617	SCV000694890	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5683G>A (p.Glu1895Lys) 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 250462 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5683G>A has been reported in the literature in individuals affected with Breast Cancer (example, Borg_2010, Capanu_2011, Wong-Brown_2015, Dong_2021). 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=5, Likely Benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590426	SCV000889073	uncertain significance	not provided	2020-07-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131358	SCV000903231	likely benign	Hereditary cancer-predisposing syndrome	2015-10-21	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000999647	SCV001135002	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-10-24	criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 11 of the BRCA2 gene that results in the amino acid substitution of Lysine for Glutamic Acid at codon 1895 was detected. The observed variation has previously been reported in patients affected with breast cancer (Borg et al 2010, Zhong et al 2016, Li et al 2017). The observed variant c.5683G>A (p.Glu1895Lys) has a minor allele frequency of 0.02% and 0.001% in the 1000 Genomes and ExAC databases respectively. The reference codon is conserved across primates. In summary, the variant meets our criteria to be classified as variant of unknown significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131358	SCV003849009	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).
MGZ Medical Genetics Center	RCV003607244	SCV004543900	likely benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000999647	SCV000591988	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The p.Glu1895Lys variant was identified in 1 of 4206 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer (Borg 2010). The variant was also identified in dbSNP (ID: rs146351301) “With Uncertain significance, untested allele”, Clinvitae database (classification uncertain significance), COSMIC (in a bladder carcinoma), the ClinVar database (classified as uncertain significance by Ambry Genetics), the BIC database (3x with unknown clinical importance), and UMD (1x with “unclassified variant”). This variant was identified in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002), HAPMAP-EAS in 1 of 1008 chromosomes (frequency: 0.001), and the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 1 of 11528 chromosomes (frequency: 0.00009) from a population of Latino individuals. The p.Glu1895 residue is not conserved in mammals and the variant amino acid Lys is present in rat, dog, cow, and opossum, increasing the likelihood that this variant does not have clinical significance; computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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.