ClinVar Genomic variation as it relates to human health

Variant summary: RAD51D c.80C>A (p.Thr27Lys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-06 in 241702 control chromosomes in the gnomAD database (exclusively found in the East Asian subpopulation). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. However, the variant was also reported in Japanese healthy controls with a frequency of 0.005, which is approximately 38-fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD51D causing Hereditary Breast and Ovarian Cancer phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian/Japanese origin (HGVD). To our knowledge, no occurrence of c.80C>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

This missense variant replaces threonine with lysine at codon 27 of the RAD51D protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 35264596). This variant also has been reported in pancreatic cancer and colorectal cancer case-control studies in 9/1005 pancreatic cancer cases and 224/23705 unaffected individuals and 100/12501 colorectal cancer cases and 224/23702 unaffected individuals, respectively (PMID: 32980694, 33309985). This variant has been identified in 2/246624 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 sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 27 of the RAD51D protein (p.Thr27Lys). This variant is present in population databases (rs139642328, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 410557). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.

The p.T27K variant (also known as c.80C>A), located in coding exon 1 of the RAD51D gene, results from a C to A substitution at nucleotide position 80. The threonine at codon 27 is replaced by lysine, an amino acid with similar properties. This variant has been identified in 100/12503 unselected Japanese colorectal cancer patients and in 224/23705 controls (Fujita M et al. Clin Gastroenterol Hepatol, 2020 Dec;:). This alteration was also detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.