ClinVar Genomic variation as it relates to human health

Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00237 (African), derived from gnomAD v2.1.1 non-cancer (2019-05-13).

This variant is associated with the following publications: (PMID: 24728327, 23415752, 12442275, 18284688, 25348012, 15001988, 15889636, 27621404, 27527004, 28526081, 30254663, 31131967)

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.

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

The BRCA2 p.Thr3374Ile variant was identified in 3 of 2236 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast and ovarian cancer and was present in 12 of 1498 control chromosomes (frequency: 0.08) from healthy individuals (Ruiz-Flores 2002, Calderon-Garciduneas 2005, Bodian 2014, Zuntini 2018). The variant was identified in dbSNP (rs56309455) as “with other allele, ClinVar (classified as likely benign by GeneDx, Color, SCRP and 2 other submitters, benign by Invitae, Ambry Genetics and Pathway Genomics and uncertain significance by BIC), LOVD 3.0 (observed 3x) and UMD-LSDB (observed 7x). The variant was identified in control databases in 79 of 282,668 chromosomes (1 homozygous) at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 59 of 24,960 chromosomes (freq: 0.002), Other in 4 of 7214 chromosomes (freq: 0.0006), Latino in 15 of 35,410 chromosomes (freq: 0.0004), European in 1 of 129,038 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish and South Asian populations. The variant was identified in our laboratory and UMD-LSDB in individuals with co-occurring pathogenic BRIP1 (c.1195G>T, p.Glu399*) and BRCA1 (c.3008_3009delTT p.Phe1003*) variants. The p.Thr3374 residue is not conserved in mammals and 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.