rs267606999

chr17-58696702-G-Cchr17-58696702-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PP3 PP5_Very_Strong

The NM_058216.3(RAD51C):c.414G>C(p.Leu138Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L138L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: RAD51C NM_058216.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 2.76

Genes affected

RAD51C (HGNC:9820): (RAD51 paralog C) This gene is a member of the RAD51 family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51 and are known to be involved in the homologous recombination and repair of DNA. This protein can interact with other RAD51 paralogs and is reported to be important for Holliday junction resolution. Mutations in this gene are associated with Fanconi anemia-like syndrome. This gene is one of four localized to a region of chromosome 17q23 where amplification occurs frequently in breast tumors. Overexpression of the four genes during amplification has been observed and suggests a possible role in tumor progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_058216.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77
• PP5: Variant 17-58696702-G-C is Pathogenic according to our data. Variant chr17-58696702-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58696702-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51C	NM_058216.3	c.414G>C	p.Leu138Phe	missense_variant	3/9	ENST00000337432.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51C	ENST00000337432.9	c.414G>C	p.Leu138Phe	missense_variant	3/9	1	NM_058216.3	P2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251476 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 06, 2023	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 22167183]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 20400964, 24993905]. -
risk factor, no assertion criteria provided	literature only	OMIM	May 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 15, 2023	- -

Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 01, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 23, 2018	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2023	Published functional studies demonstrate a damaging effect: impaired response to DNA damage, reduced RAD51 foci formation, impaired protein interaction with RAD51 paralogs, increased chromosome aberrations, and inability to rescue cell survival (Meindl et al., 2010; Somyajit et al., 2012; Somyajit et al., 2013; Prakash et al., 2022); Observed in individuals with history consistent with pathogenic variants in this gene (Loveday et al., 2012; Osorio et al., 2012; Spugnesi et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20952512, 27328445, 22451500, 25470109, 20400964, 29922827, 28888541, 26678223, 24993905, 26354865, 22167183, 23438602, 24141787, 21537932, 28829762, 30612635, 25292178, 22538716, 35565380, 14704354, 36562461, 36099300) -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Nov 02, 2014	Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 03, 2023	This missense variant replaces leucine with phenylalanine at codon 138 of the RAD51C protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Multiple functional studies have shown that the mutant protein exhibits significantly reduced ability to bind BRCA2, RAD51D, RAD51B, and XRCC3, reduced homologous recombination activity, and inability to complement RAD51C deficiency in cell survival assay (PMID: 20400964, 22167183, 24141787, 25292178, 36099300). This variant has been reported in five unrelated individuals affected with ovarian cancer with family history of ovarian cancer and/or breast cancer (PMID: 20400964, 22451500, 24993905, 35565380). This variant has also been reported in an individual with sporadic, early-onset ovarian cancer (PMID: 35565380) and in an individual with triple-negative breast cancer (PMID: 27328445). This variant has been identified in 1/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 26, 2023	The p.L138F variant (also known as c.414G>C), located in coding exon 3 of the RAD51C gene, results from a G to C substitution at nucleotide position 414. The leucine at codon 138 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was previously described and found to co-segregate in one German breast and ovarian cancer family, and LOH was present in 3/3 tumors available (2 ovarian cancers and 1 breast cancer) (Meindl A et al. Nat. Genet. 2010 May; 42(5):410-4). This alteration was also reported in a Spanish female diagnosed with ovarian cancer at age 62; one of her sisters was diagnosed with breast cancer at age 37 and a second sister, who also had this variant, was diagnosed with bilateral breast cancer at ages 64 and 72, and was not reported in 550 healthy controls with no family history of cancer (Osorio A et al. Hum. Mol. Genet. 2012 Jul; 21(13):2889-98). This variant has been identified in multiple individuals diagnosed with ovarian cancer (Alenezi WM et al. Cancers (Basel), 2022 Apr;14; Loveday C et al. Nat Genet, 2012 Apr;44:475-6). In multiple assays testing RAD51C function, this variant showed functionally abnormal results (Meindl A et al. Nat. Genet. 2010 May; 42(5):410-4; Somyajit K et al. J. Biol. Chem. 2012 Jan; 287(5):3366-80; Park JY et al. Oncogene 2014 Oct; 33(40):4803-12; Somyajit K et al. Carcinogenesis 2015 Jan; 36(1):13-24; Somyajit K et al. Nucleic Acids Res. 2015 Nov; 43(20):9835-55; Prakash R et al. Proc Natl Acad Sci U S A, 2022 Sep;119:e2202727119; Hu C et al. Cancer Res, 2023 Aug;83:2557-2571). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Fanconi anemia complementation group O Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 138 of the RAD51C protein (p.Leu138Phe). This variant is present in population databases (rs267606999, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 20400964, 22451500, 22538716, 27328445). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6825). 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 expected to disrupt RAD51C protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RAD51C function (PMID: 20400964, 22167183, 24141787, 25292178, 26354865). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 14, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Uncertain	23
Dann	Benign	0.92
DEOGEN2	Benign	0.077	T;T;T;T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D
MetaSVM	Benign	-0.54	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		0.99	.;.;D;.;.
Vest4		0.90, 0.89
MutPred		0.92		.;Gain of loop (P = 0.2045);Gain of loop (P = 0.2045);.;.;
MVP		0.84
MPC		0.87
ClinPred		0.97	D
GERP RS		2.6
Varity_R		0.76
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267606999; hg19: chr17-56774063;