ClinVar Genomic variation as it relates to human health

Variant summary: BRCA2 c.2274T>G (p.Ser758Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251204 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2274T>G has been reported in the literature in individuals affected with breast cancer (examples: Fernandes_2016, Guindalini_2022 ) or upper tract urothelial carcinoma (Vlachostergios_2020). These reports 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: 27741520, 35264596). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=3) and VUS (n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.

This alteration is classified as 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.

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

In the published literature, this variant has been reported in individuals with breast cancer (PMID: 35264596 (2022), 27741520 (2016)). The frequency of this variant in the general population, 0.00036 (9/24956 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

Observed in individuals with breast or ovarian cancer (PMID: 27741520, 37664050, 35264596); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 2502T>G; This variant is associated with the following publications: (PMID: 29884841, 31911673, 32377563, 35264596, 27741520, 37664050)

The BRCA2 p.Ser758Arg variant was identified in 1 of 698 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Fernandes 2016). The variant was also identified in dbSNP (ID: rs142243359) as "With Likely benign, Uncertain significance allele", ClinVar (classified as benign by Ambry Genetics; as uncertain significance by Invitae, GeneDx and two clinical laboratories), and in LOVD 3.0 (2x). The variant was not identified in UMD-LSDB database. The variant was identified in control databases in 10 of 277004 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 8 of 24030 chromosomes (freq: 0.0003), Latino in 2 of 34376 chromosomes (freq: 0.00006), while the variant was not observed in the Other, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ser758 residue is not conserved in mammals and four out of five 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. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.