ENST00000421782.3:c.404G>C

Variant names:

• chr17-58695189-G-C
• rs767796996
• ENST00000421782.3:c.404G>C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The ENST00000421782.3(RAD51C):​c.404G>C​(p.Trp135Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W135R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD51C ENST00000421782.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.75

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 16 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, 8 uncertain in ENST00000421782.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-58695189-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 942269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-58695189-G-C is Pathogenic according to our data. Variant chr17-58695189-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 418441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51C	NM_058216.3	c.404G>C	p.Cys135Ser	missense_variant, splice_region_variant	Exon 2 of 9	ENST00000337432.9	NP_478123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9	c.404G>C	p.Cys135Ser	missense_variant, splice_region_variant	Exon 2 of 9	1	NM_058216.3	ENSP00000336701.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Apr 20, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 27622768 (2017)). In a large-scale breast cancer association study, the variant was seen in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD51C)). Published functional studies show that this variant creates an aberrant isoform resulting in reduced expression levels of the RAD51C protein in affected individuals (PMID: 27622768 (2017)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

Oct 25, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with personal and family history of breast or ovarian cancer (PMID: 27622768); Located at the last nucleotide of the exon and demonstrated to result in aberrant splicing (PMID: 33333735, 27622768); This variant is associated with the following publications: (PMID: 27622768, 31782267, 33333735, 14704354, 31341520, 34923718) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Aug 14, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.404G>C pathogenic mutation (also known as p.C135S), located in coding exon 2 of the RAD51C gene, results from a G to C substitution at nucleotide position 404. The amino acid change results in cysteine to serine at codon 135, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA analyses have shown that this alteration leads to the insertion of 27 nucleotides of intronic sequence between exons 2 and 3 and introduces a premature stop codon (Neidhardt G et al. Eur. J. Cancer Prev. 2017 Mar;26:165-169, Ambry internal data). This alteration has been identified in two female probands with breast cancer and family histories of breast or breast and ovarian cancer (Neidhardt G et al. Eur. J. Cancer Prev. 2017 Mar;26:165-169). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Apr 26, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to C nucleotide substitution at the last nucleotide of exon 2 of the RAD51C gene and replaces cysteine with serine at codon 135 of the RAD51C protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. An RNA study using carrier-derived RNA has shown that the variant leads to the use of an alternative splice donor site, resulting in the inclusion of the first 27 nucleotides of intron 2 in the RNA transcript (PMID: 27622768). The aberrant transcript is predicted to create a premature translation stop signal and is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 27622768). 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 Likely Pathogenic. -

Fanconi anemia complementation group O Pathogenic:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 135 of the RAD51C protein (p.Cys135Ser). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 27622768; internal data). ClinVar contains an entry for this variant (Variation ID: 418441). 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 disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 27622768; internal data). This variant disrupts the c.404G nucleotide in the RAD51C gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 22451500, 27622768, 29409816; internal data). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Dec 23, 2019

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Aug 17, 2023

Human Genetics Bochum, Ruhr University Bochum

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria used to clasify this variant:PVS1_STR, PM5, PS3_SUP, PS4_SUP, PM2_SUP, PP3 -

Jan 02, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 27622768]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	33
DANN	Benign	0.84
DEOGEN2	Benign	0.048	T;T;T;T;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.8	.;.;L;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.5	.;.;D;D;.
REVEL	Uncertain	0.44
Sift	Benign	0.48	.;.;T;T;.
Sift4G	Benign	0.53	T;T;T;T;T
Polyphen		0.59	.;.;P;.;.
Vest4		0.84, 0.85
MutPred		0.78		.;Gain of disorder (P = 0.0403);Gain of disorder (P = 0.0403);.;.;
MVP		0.82
MPC		0.86
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.58
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.29		Position offset: -22
DS_DL_spliceai		0.94		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs767796996; hg19: chr17-56772550;