Submissions for variant NM_000059.4(BRCA2):c.6560C>T (p.Pro2187Leu)

gnomAD frequency: 0.00015  dbSNP: rs56019712

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081092	SCV000072998	benign	Hereditary breast ovarian cancer syndrome	2025-02-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129413	SCV000184183	likely benign	Hereditary cancer-predisposing syndrome	2018-01-31	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	RCV000589601	SCV000210631	likely benign	not provided	2021-06-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24651015)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589601	SCV000600712	likely benign	not provided	2022-04-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129413	SCV000688987	likely benign	Hereditary cancer-predisposing syndrome	2015-04-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044985	SCV000694981	likely benign	not specified	2024-03-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6560C>T (p.Pro2187Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 246842 control chromosomes, predominantly at a frequency of 0.00083 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.6560C>T has been reported in the literature in individuals affected with, or suspected as having breast cancer (Briceno-Balcazar_2017, Ren_2021) but it was also reported in unaffected controls (Dorling_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. The following publications have been ascertained in the context of this evaluation (PMID: 29021639, 33471991, 34196900). ClinVar contains an entry for this variant (Variation ID: 38052). Based on the evidence outlined above, the variant was classified as likely benign.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001081092	SCV000891014	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-08-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000031634	SCV001267261	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-11-26	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001109884	SCV001267262	uncertain significance	Fanconi anemia complementation group D1	2018-11-26	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics	RCV001109884	SCV001522806	uncertain significance	Fanconi anemia complementation group D1	2019-05-29	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589601	SCV002049876	uncertain significance	not provided	2022-01-10	criteria provided, single submitter	clinical testing	The BRCA2 c.6560C>T; p.Pro2187Leu variant (rs56019712), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 38052). This variant is found in the Latino population with an overall allele frequency of 0.08% (29/34630 alleles) in the Genome Aggregation Database. The proline at codon 2187 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.336). Given the lack of clinical and functional data, the significance of the p.Pro2187Leu variant is uncertain at this time.
Sema4, Sema4	RCV000129413	SCV002536244	likely benign	Hereditary cancer-predisposing syndrome	2021-07-14	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129413	SCV003847271	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).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492317	SCV004240341	uncertain significance	Breast and/or ovarian cancer	2023-01-12	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031634	SCV000054241	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-11-11	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031634	SCV000146884	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing