ClinVar Genomic variation as it relates to human health

This variant is associated with the following publications: (PMID: 24651015)

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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.

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.

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.

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

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.

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.