ClinVar Genomic variation as it relates to human health

Variant summary: BRCA2 c.7598C>G (p.Ser2533Cys) results in a non-conservative amino acid change located in the helical domain (IPR015252) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250848 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.7598C>G, has been reported in the literature in individuals affected with breast and/or ovarian cancer (e.g., Tung_2014, Maxwell_2016) and also in an individual affected with endometrial cancer (e.g., Ring_2016), however without strong evidence for causality (e.g., lack of co-segregation data). These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one co-occurrence with another pathogenic variant has been observed in internal testing (BRCA1 c.135-1G>T), providing supporting evidence for a benign role. The variant has been demonstrated in several functional studies to have no damaging effect on homology-directed DNA repair (HDR) activity (e.g., Hart_2019, Richardson_2021, Hu_2022). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group (PMID: 31892348). ClinGen SVI now recognizes strong functional evidence (ACMG BS3) as sufficient for categorization as likely benign (PMID: 29300386). The following publications have been ascertained in the context of this evaluation (PMID: 31191615, 29884841, 35736817, 19043619, 27153395, 33609447, 27443514, 25186627, 30447919). ClinVar contains an entry for this variant (Variation ID: 38108). Based on the evidence outlined above, the variant was classified as likely benign.

This variant is denoted BRCA2 c.7598C>G at the cDNA level, p.Ser2533Cys (S2533C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). This variant, also known as BRCA2 7826C>G using alternate nomenclature, has been reported in at least one individual with breast and/or ovarian cancer and one with endometrial cancer (Maxwell 2016, Ring 2016). BRCA2 Ser2533Cys was not observed at a significant frequency in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ser2533Cys occurs at a position that is not conserved and is located in the DNA binding domain and region of interaction with FANCD2 (Yang 2002, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Ser2533Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

This missense variant replaces serine with cysteine at codon 2533 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown this variant does not impact homology-directed DNA repair activity (PMID: 29884841, 33609447, 35736817). This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 27153395, 33471991; Leiden Open Variation Database DB-ID BRCA2_000213) and an individual affected with endometrial cancer (PMID: 27443514). This variant has been identified in 2/250848 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 function. This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2533 of the BRCA2 protein (p.Ser2533Cys). This variant is present in population databases (rs80358987, gnomAD 0.003%). This missense change has been observed in individual(s) with endometrial cancer (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 38108). Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 29884841). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This missense variant replaces serine with cysteine at codon 2533 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown this variant does not impact homology-directed DNA repair activity (PMID: 29884841, 33609447, 35736817). This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 27153395, 33471991; Leiden Open Variation Database DB-ID BRCA2_000213) and an individual affected with endometrial cancer (PMID: 27443514). This variant has been identified in 2/250848 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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.