ClinVar Genomic variation as it relates to human health

Variant summary: RAD51C c.224dupA (p.Tyr75X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., p.Gln133X and p.Arg193X). The variant was absent in 246238 control chromosomes. c.224dupA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant duplicates 1 nucleotide in exon 2 of the RAD51C 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 ovarian cancer (PMID: 20400964, 22006311, 24240112, 24993905, 26720728, 27230542, 29053726) and breast cancer (PMID: 26681312, 26848151, 29522266). This variant has been identified in 3/251456 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51C function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

ACMG Criteria: PVS1, PM2, PP3, PP4, PP5_S; Variant was found in heterozygous state

The c.224dupA pathogenic mutation, located in coding exon 2 of the RAD51C gene, results from a duplication of A at nucleotide position 224, causing a translational frameshift with a predicted alternate stop codon (p.Y75*). This mutation has been reported in multiple individuals with breast or ovarian cancer, including individuals who also had a family history of breast and/or ovarian cancer (Meindl A et al. Nat Genet, 2010 May;42:410-4; Walsh T et al. Proc Natl Acad Sci U S A, 2011 Nov;108:18032-7; Wolf C et al. Nat Commun, 2016 May;7:11752; Norquist BM et al. JAMA Oncol, 2016 Apr;2:482-90; Susswein LR et al. Genet Med, 2016 08;18:823-32; Villalona-Calero MA et al. J Natl Cancer Inst, 2016 Jul;108; Harter P et al. PLoS One, 2017 Oct;12:e0186043; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Weber-Lassalle K et al. Hum Mutat, 2018 12;39:2040-2046; Suszynska M et al. J Ovarian Res, 2020 May;13:50; Fanale D et al. Cancers (Basel), 2020 Aug;12; Dorling et al. N Engl J Med. 2021 02;384:428-439). In a cohort of 3030 pancreatic cancer patients undergoing multigene panel testing, this variant was seen in two cases (Hu C et al. JAMA. 2018 06;319:2401-2409). This alteration has also been reported in a patient with acute myeloid leukemia from a cohort of 4034 cancer cases from The Cancer Genome Atlas (Lu C et al. Nat Commun. 2015 Dec 22;6:10086). 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.

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

This variant has been identified by standard clinical testing. female patient with triple negativ breast cancer Selected ACMG criteria: Pathogenic (I):PP5;PS4;PVS1

This sequence change creates a premature translational stop signal (p.Tyr75*) in the RAD51C gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD51C are known to be pathogenic (PMID: 20400964, 21990120, 24800917, 29278735). This variant is present in population databases (rs730881939, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 20400964, 22006311, 26681312, 26848151). This variant is also known as c.224insA, c.223_224insA, and 224_225insA. ClinVar contains an entry for this variant (Variation ID: 182844). For these reasons, this variant has been classified as Pathogenic.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 20400964, 22006311, 26848151, 27230542, 35626031); This variant is associated with the following publications: (PMID: 24800917, 26681312, 26848151, 29922827, 28888541, 27230542, 20400964, 22006311, 30216591, 29625052, 26689913, 32854451, 35626031, 35988656, 36493725, 29053726, 33471991, 36451132)

Curator: Arleen D. Auerbach. Submitters to LOVD: Christine Rappaport, Johan den Dunnen.

Variant interpreted as Pathogenic and reported on 03-04-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.