Submissions for variant NM_000059.4(BRCA2):c.9175A>G (p.Lys3059Glu)

dbSNP: rs80359174

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000114059	SCV001161628	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000879
Invitae	RCV001079907	SCV000073750	likely benign	Hereditary breast ovarian cancer syndrome	2023-11-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130061	SCV000184888	likely benign	Hereditary cancer-predisposing syndrome	2018-03-30	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.
GeneDx	RCV000766656	SCV000278886	likely benign	not provided	2020-06-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19043619, 31131967)
Counsyl	RCV000114059	SCV000488180	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-01-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130061	SCV000903036	likely benign	Hereditary cancer-predisposing syndrome	2017-09-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000217640	SCV000918983	likely benign	not specified	2022-10-10	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9175A>G (p.Lys3059Glu) results in a conservative amino acid change located in the BRCA2, OB3 domain of 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 4e-06 in 251304 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Although seen in the literature, to our knowledge, no occurrence of c.9175A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. At-least two co-occurrences with other pathogenic variant(s) have been ascertained in the BIC database and at our laboratory (BIC database-BRCA2 c.8237_8238delCA, p.Thr2746Serfs; our laboratory-BRCA2 c.8575delC, p.Q2859fsX4), providing supporting evidence for a benign role. Five clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as likely benign/benign (n=6, expert panel benign) (VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003934986	SCV004756797	uncertain significance	BRCA2-related condition	2024-01-13	criteria provided, single submitter	clinical testing	The BRCA2 c.9175A>G variant is predicted to result in the amino acid substitution p.Lys3059Glu. To our knowledge, this variant has not been reported in the literature in affected individuals. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has varied interpretations in ClinVar, ranging from uncertain to benign, with the ENIGMA expert panel interpreting it as benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/52767/; Supplemental Table 1, Parsons et al. 2019. PubMed ID: 31131967). While we suspect this variant could be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000114059	SCV000147558	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000114059	SCV000297577	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-07-05	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353881	SCV000592262	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Lys3059Glu variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, ARUP Laboratories, and Zhejiang Colon Cancer databases. The variant was identified in dbSNP (ID: rs80359174) as “With other allele”; in ClinVar and Clinvitae as likely benign by Invitae, Ambry Genetics, Sharing Clinical Reports Project, and with uncertain significance by GeneDx and Counsyl. In addition, the variant was listed in the BIC database 3X with unknown significance; in LOVD 3.0 database 1X with no classification; in the UMD-LSDB database 2X as uncertain significance with no co-occurrence of other pathogenic variants; and in the BIC Database 3X with unknown significance. The variant was also identified by our laboratory in 2 individuals with breast cancer. Furthermore, the variant was identified in control databases in 1 of 246114 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). It was identified in the European Non-Finnish population in 1 of 111604 chromosomes (freq: 0.000009), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. In silico predicted impact on the protein is uncertain (Karchin_2008). The p.Lys3059 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.