ClinVar Genomic variation as it relates to human health

This deletion of one nucleotide in RAD51D is denoted c.363delA at the cDNA level and p.Ala122GlnfsX14 (A122QfsX14) at the protein level. The normal sequence, with the base that is deleted in brackets, is TGGC[delA]GCAA. The deletion causes a frameshift, which changes an Alanine to a Glutamine at codon 122, and creates a premature stop codon at position 14 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. RAD51D c.363delA has been seen in a woman with bilateral breast cancer and a family history of ovarian, colon and prostate cancer (Loveday 2011). We consider this variant to be pathogenic.

The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

This variant deletes 1 nucleotide in exon 5 of the RAD51D gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 21822267, 26681312, 29470806, 32885271). This variant has been identified in 4/251416 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51D function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

This sequence change creates a premature translational stop signal (p.Ala122Glnfs*14) in the RAD51D gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD51D are known to be pathogenic (PMID: 21822267). This variant is present in population databases (rs730881935, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with early onset breast cancer (PMID: 21822267). ClinVar contains an entry for this variant (Variation ID: 182840). For these reasons, this variant has been classified as Pathogenic.

The RAD51D c.423del(p.Ala142GlnfsTer14) variant has been reported in heterozygous state in individuals affected with Breast-Ovarian Cancer (Loveday C et al). This variant has been reported allele frequency 0.001591% in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant causes a frameshift starting with codon Alanine 142, changes this amino acid to Glutamine residue, and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Ala142GlnfsTer14. Loss-of-function variants in RAD51D are known to be pathogenic. For these reasons, this variant has been classified as Pathogenic.

The c.363delA pathogenic mutation, located in coding exon 5 of the RAD51D gene, results from a deletion of one nucleotide at nucleotide position 363, causing a translational frameshift with a predicted alternate stop codon (p.A122Qfs*14). This mutation has been reported in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Loveday C et al. Nat. Genet. 2011 Aug;43:879-82; Susswein LR et al. Genet Med, 2016 08;18:823-32; Yang X et al. J Natl Cancer Inst, 2020 12;112:1242-1250; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

The RAD51D p.Ala122Glnfs*14 variant was identified in 1 of 1922 proband chromosomes (frequency: 0.0005) from individuals or families with breast cancer (Loveday 2011). The variant was also identified in dbSNP (ID: rs730881935) as "With Pathogenic allele", ClinVar (classified as pathogenic by GeneDx, Ambry Genetics, Invitae and one other submitter; and as likely pathogenic by Counsyl). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.363del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 122 and leads to a premature stop codon at position 135. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the RAD51D gene are an established mechanism of disease in RAD51D-associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.