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 1 based on posterior probability = 1.80E-06

The BRCA2 c.9038C>T; p.Thr3013Ile variant (rs28897755) has been reported in the literature in individuals with a personal or family history of hereditary breast and ovarian cancer (Houdayer 2012, Malone 2000, Sanz 2010). However, this variant has also been found incidentally in an individual with no personal or family history of cancer (Johnston 2012). This variant is reported with conflicting interpretations of pathogenicity in ClinVar, with most sources classifying as benign or likely benign (Variation ID: 38205) and is seen in the general population at an overall frequency of 0.02% (65/276280 alleles, including 1 homozygote) in the Genome Aggregation Database. The threonine at codon 3013 is moderately conserved but computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to have no impact on protein function. In agreement with this, functional analysis of this variant protein shows no defects in DNA double-strand break repair using a cell-based homology directed repair assay (Guidugli 2013). Based on the above information, this variant is considered likely benign. REFERENCES Guidugli L et al. A classification model for BRCA2 DNA binding domain missense variants based on homology directed repair activity. Cancer Res. 2013 Jan 1; 73(1): 265–275. Houdayer C et al. Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. Hum Mutat. 2012 Aug;33(8):1228-38. Johnston J et al. Secondary Variants in Individuals Undergoing Exome Sequencing: Screening of 572 Individuals Identifies High-Penetrance Mutations in Cancer-Susceptibility Genes. Am J Hum Genet. 2012 Jul 13; 91(1): 97–108. Malone K et al. Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases. Cancer. 2000 Mar 15;88(6):1393-402. Sanz D et al. A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. Clin Cancer Res. 2010 Mar 15;16(6):1957-67.

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.

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 8 B/LB

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

The BRCA2 c.9038C>T variant is classified as Benign (BS1, BS3, BP4, BP6)

BRCA2: BP4, BS3:Supporting

Converted during submission to Likely benign.

The BRCA2 p.Thr3013Ile variant was identified in 5 of 2946 proband chromosomes (frequency: 0.002) from individuals with breast or ovarian cancer (Claes 2004, Diez 2003, Kim 2005). This variant was listed in dbSNP (ID: rs28897755) “With probable-non-pathogenic allele”, and in the Exome Variant Server ESP project with a frequency of 0.0004. It was identified in several populations from the HapMap project, including: HAPMAP-MEX (frequency: 0.03), HapMap-JPT (frequency: 0.012), and HapMap-HCB (frequency: 0.012), increasing the likelihood that this is a low frequency benign variant in certain populations of origin. The variant was also identified in the following databases: HGMD, LOVD, BIC (53X with no clinical importance), and UMD (13X as a neutral variant). In UMD it was twice reported to co-occur with pathogenic mutations in the BRCA1 or BRCA2 genes (BRCA2 c.1257delT (p.Cys419TrpfsX11), BRCA1 c.5266dup (p.Gln1756ProfsX74)), increasing the likelihood that this variant does not have clinical significance. In addition, in silico studies and functional studies predict this that this variant has a neutral effect on BRCA2 protein function (Guidugli 2013, Karachin 2008). The p.Thr3013 residue is not conserved in mammals and lower organisms, and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein but this information is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.