Submissions for variant NM_058216.3(RAD51C):c.732del (p.Ile244fs)

dbSNP: rs1060502601

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000471345	SCV000550222	pathogenic	Fanconi anemia complementation group O	2023-09-10	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 26261251, 26720728). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile244Metfs*9) 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 also known as c.731delT. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 409860).
GeneDx	RCV000486595	SCV000569471	likely pathogenic	not provided	2016-04-08	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in RAD51C is denoted c.732delT at the cDNA level and p.Ile244MetfsX9 (I244MfsX9) at the protein level. The normal sequence, with the base that is deleted in braces, is GTAT[T]GCTT. The deletion causes a frameshift which changes an Isoleucine to a Methionine at codon 244, and creates a premature stop codon at position 9 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. RAD51C c.732delT, also known as 731delT using alternate nomenclature, has been observed in at least two individuals with a personal and family history of ovarian and/or breast cancer (Song 2015). Based on the currently available information, we consider this deletion to be a likely pathogenic variant.
Counsyl	RCV000576324	SCV000677833	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2017-03-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589098	SCV000699821	likely pathogenic	Hereditary breast ovarian cancer syndrome	2016-12-16	criteria provided, single submitter	clinical testing	Variant summary: The RAD51C c.732delT (p.Ile244Metfs) variant results in a premature termination codon, predicted to cause a truncated or absent RAD51C protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/130846 control chromosomes at a frequency of 0.0000076, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625). The variant was reported in two affected individuals and one control individual from the literature (Song_2015, Norquist_2016). While this variant is predicted to be pathogenic, more clinical or functional data is needed to definitively classify this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000775758	SCV000910195	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 5 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 not been identified 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.
Ambry Genetics	RCV000775758	SCV001188627	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-20	criteria provided, single submitter	clinical testing	The c.732delT pathogenic mutation, located in coding exon 5 of the RAD51C gene, results from a deletion of one nucleotide at nucleotide position 732, causing a translational frameshift with a predicted alternate stop codon (p.I244Mfs*9). This alteration has been reported in a cohort of women with invasive epithelial ovarian cancer (Song H et al. J. Clin. Oncol., 2015 Sep;33:2901-7). 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.
Myriad Genetics, Inc.	RCV003316570	SCV004019969	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2023-04-05	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000486595	SCV004026262	likely pathogenic	not provided	2023-02-10	criteria provided, single submitter	clinical testing	PM4, PS4, PM2_SUP
Baylor Genetics	RCV003316570	SCV004208034	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 3	2022-07-06	criteria provided, single submitter	clinical testing