ClinVar Genomic variation as it relates to human health

This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 2434 of the BRCA2 protein (p.Lys2434Thr). This variant is present in population databases (rs80358954, gnomAD 0.03%). This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 24448499, 25036526, 26689913, 27495310, 29470806, 30555256). ClinVar contains an entry for this variant (Variation ID: 52304). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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 lysine with threonine at codon 2434 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 24448499, 25036526, 27495310, 29470806, 30555256, 35402282). This variant has also been identified in 8/251234 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.

In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as 7529A>C; This variant is associated with the following publications: (PMID: 25036526, 24448499, 26689913, 29470806, 27495310, 30555256, 32377563, 29884841, 35402282)

This missense variant replaces lysine with threonine at codon 2434 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 24448499, 25036526, 27495310, 29470806, 30555256, 35402282). This variant has also been identified in 8/251234 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.

The BRCA2 p.Lys2434Thr variant was identified in 1 of 858 proband chromosomes (frequency: 0.001) from individuals or families with ovarian cancer and was not identified in 1114 control chromosomes from healthy individuals (Kanchi 2014). The variant was also identified in dbSNP (ID: rs80358954) as “With Uncertain significance allele”, ClinVar (4x as uncertain significance by GeneDx, Ambry Genetics, BIC, University Hospital of Norway). The variant was not identified in LOVD 3.0 or UMD-LSDB. The variant was identified in control databases in 8 of 246012 chromosomes at a frequency of 0.000033 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: and South Asian in 8 of 30780 chromosomes (freq: 0.00026), it was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian or European Finnish populations. The p.Lys2434Thr 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.