ClinVar Genomic variation as it relates to human health

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.995729

This sequence change affects a donor splice site in intron 2 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and is likely to result in the loss of the initiator methionine. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12938098, 29446198, 31706072). This variant is also known as IVS2+1G>T. ClinVar contains an entry for this variant (Variation ID: 52161). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 31131967). Studies have shown that disruption of this splice site results in skipping of exon 2, and is expected to result in the loss of the initiator methionine (PMID: 17011978, 22505045, 30883759). This variant disrupts the p.Met1 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20104584, 21203900, 21769658, 24607278, 24916970). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Variant summary: BRCA2 c.67+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict that the variant abolishes a 5 splicing donor site. Experimental evidence demonstrates that this variant affects mRNA splicing by skipping of exon 2 completely (Fraile-Bethencourt_2019, Houdayer_2012). The variant was absent in 250582 control chromosomes (gnomAD). c.67+1G>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Meyer_2003, Rebbeck_2018, Zugazagoitia_2014). These data indicate that the variant is likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant causes a G to T nucleotide substitution at the +1 position of intron 2 of the BRCA2 gene. Functional RNA studies have shown that this variant causes skipping of exon 2, expected to result in the loss of the initiator methionine. This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 25342642, 31706072, doi.org/10.1515/tjb-2019-0424). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

The c.67+1G>T variant in the BRCA2 gene is located at the canonical splice site of intron 2 and is predicted to inflict donor loss (SpliceAI delta score: 0.98), resulting in alternative splicing and disrupted protein product. The variant has been reported in multiple individuals with breast/ovarian/prostate cancer (PMID: 32846166, 31512090, 32438681, 35892882, 12938098). Experimental study of this variant showed skipping of exon 2 (PMID: 12938098). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 52161) and reviewed by the expert panel. The variant is absent in the general population database (gnomAD). Therefore, the c.67+1G>T variant of BRCA2 has been classified as pathogenic.

The c.67+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 1 of the BRCA2 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This variant, as well as several close match variants at this donor site have been shown by multiple assays to result in skipping of coding exon 1 (also known as exon 2) with resulting predicted loss of the translational start codon (Ambry internal data; Houdayer C et al. Hum. Mutat., 2012 Aug;33:1228-38; Parsons MT et al. Mol Carcinog, 2015 Jul;54:513-22; Feben C et al. Fam Cancer, 2017 07;16:441-446; Fraile-Bethencourt E et al. J Pathol, 2019 08;248:409-420). This alteration was also classified as pathogenic in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence and tumor pathology and case-control data (Parsons MT et al. Hum Mutat, 2019 Sep;40:1557-1578). This variant was reported in multiple individuals with features consistent with BRCA2-related hereditary breast and ovarian cancer syndrome (Meyer P et al. Hum Mutat, 2003 Sep;22:259; Rebbeck TR et al. Hum Mutat, 2018 May;39:593-620; Mondschein R et al. Cancers (Basel), 2022 Jul;14). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.