Submissions for variant NM_058216.3(RAD51C):c.1109G>A (p.Arg370Gln)

gnomAD frequency: 0.00001  dbSNP: rs373170458

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166749	SCV000217560	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-08	criteria provided, single submitter	clinical testing	The p.R370Q variant (also known as c.1109G>A), located in coding exon 9 of the RAD51C gene, results from a G to A substitution at nucleotide position 1109. The arginine at codon 370 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168186	SCV000218849	uncertain significance	Fanconi anemia complementation group O	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 370 of the RAD51C protein (p.Arg370Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. ClinVar contains an entry for this variant (Variation ID: 187061). 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 tolerated. 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.
Color Diagnostics, LLC DBA Color Health	RCV000166749	SCV000691218	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 370 of the RAD51C 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. In a large breast cancer case-control study, this variant has been observed in 6/60460 cases and 2/53459 controls; OR=2.653 (95%CI 0.535 to 13.143); p-value=0.296 (PMID: 33471991 - Leiden Open Variation Database DB-ID RAD51C_000235). This variant has been identified in 3/248394 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.
Counsyl	RCV000662686	SCV000785405	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2017-08-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192875	SCV001361300	uncertain significance	not specified	2019-09-13	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.1109G>A (p.Arg370Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 248394 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1109G>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284225	SCV001469890	uncertain significance	not provided	2020-05-04	criteria provided, single submitter	clinical testing
GeneDx	RCV001284225	SCV001793927	uncertain significance	not provided	2024-11-07	criteria provided, single submitter	clinical testing	Observed in cases but also in controls in a breast cancer case-control study (PMID: 33471991); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12966089, 14704354, 33471991)
Sema4, Sema4	RCV000166749	SCV002531789	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-04	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150028	SCV003837701	uncertain significance	Breast and/or ovarian cancer	2021-08-09	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003153453	SCV003843149	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2022-11-08	criteria provided, single submitter	clinical testing	The RAD51C c.1109G>A (p.Arg370Gln) missense change has a maximum subpopulation frequency of 0.0027% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in at least six individuals with breast cancer and in two unaffected control individuals (PMID: 33471991, Leiden Open Variation Database). This variant is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Myriad Genetics, Inc.	RCV003153453	SCV004019946	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-04-05	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV003153453	SCV004209758	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2024-02-05	criteria provided, single submitter	clinical testing