ClinVar Genomic variation as it relates to human health

The RAD51D c.412A>C; p.Asn138His variant (rs141690729) is reported in the literature in an individual with ovarian cancer (Konstanta 2018), and is reported in ClinVar (Variation ID: 127888). A different variant at this codon (p.Asn138Ser) is also reported in the literature in an individual with ovarian cancer, but was also found in a healthy control individual (Sanchez-Bermudez 2018). The p.Asn138His variant is found in the general population with an overall allele frequency of 0.004% (12/282832 alleles) in the Genome Aggregation Database. The asparagine at codon 138 is moderately conserved, but computational analyses (SIFT: Tolerated, PolyPhen-2: Possibly Damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Konstanta I et al. Contribution of RAD51D germline mutations in breast and ovarian cancer in Greece. J Hum Genet. 2018 Nov;63(11):1149-1158. Sanchez-Bermudez AI et al. Mutational analysis of RAD51C and RAD51D genes in hereditary breast and ovarian cancer families from Murcia (southeastern Spain). Eur J Med Genet. 2018 Jun;61(6):355-361.

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31159747, 21111057, 14704354, 19327148, 30111881)

This missense variant replaces asparagine with histidine at codon 138 of the RAD51D 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 an individual affected with ovarian cancer (PMID: 30111881), in an individual with breast cancer (PMID: 36011273), and in five individuals with a personal or family history of breast and/or ovarian cancer (PMID: 31159747). In a large breast cancer case-control study, this variant was identified in 2/60464 cases and 0/53461 controls (PMID: 33471991 - Leiden Open Variation Database DB-ID RAD51D_000146). This variant has also been identified in 12/282832 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 asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 138 of the RAD51D protein (p.Asn138His). This variant is present in population databases (rs141690729, gnomAD 0.009%). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 30111881, 31159747). ClinVar contains an entry for this variant (Variation ID: 127888). 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 RAD51D protein function with a negative predictive value of 80%. 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.N138H variant (also known as c.412A>C), located in coding exon 5 of the RAD51D gene, results from an A to C substitution at nucleotide position 412. The asparagine at codon 138 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in an ovarian cancer patient from a Greek breast and/or ovarian cancer cohort (Konstanta I et al. J. Hum. Genet., 2018 Nov;63:1149-1158) and in a colorectal cancer patient from a Turkish breast and/or colorectal cancer cohort, listed as a variant of unknown significance (Akcay IM et al. Int J Cancer 2021 01;148(2):285-295). It has also been reported as a variant of unknown significance in 5/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is poorly 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.

RAD51D: BP1, BP4