17-58695189-G-T

Position:

• chr17-58695189-G-T

Variant summary

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

The NM_058216.3(RAD51C):​c.404G>T​(p.Cys135Phe) variant causes a missense, splice region 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. 1/1 splice prediction tools predicting alterations to normal splicing. 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. C135R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD51C NM_058216.3 missense, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_058216.3
• 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-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.
• 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-T is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51C	NM_058216.3	c.404G>T	p.Cys135Phe	missense_variant, splice_region_variant	2/9	ENST00000337432.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51C	ENST00000337432.9	c.404G>T	p.Cys135Phe	missense_variant, splice_region_variant	2/9	1	NM_058216.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2017

The c.404G>T pathogenic mutation, located in coding exon 2 of the RAD51C gene, results from a G to T substitution at nucleotide position 404. This change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. This alteration was identified in 1/610 German breast only or breast and ovarian families. The index case in this family had ovarian cancer at 70, and a sister with ovarian cancer at 57 who was not tested for the alteration. RT-PCR analysis followed by Sanger sequencing confirmed that this alteration disrupts normal splicing at the donor site of exon 2 leading to missense substitution followed by immediately by a stop codon (p.Cys135Leufs*2) (Neidhardt G et al. Eur. J. Cancer Prev. 2017 Mar;26:165-169). Two additional alterations have been identified in breast and ovarian families at this position, one of which was also confirmed to disrupt mRNA splicing leading to a truncated protein (Neidhardt G et al. Eur. J. Cancer Prev. 2017 Mar;26:165-169; Osorio A et al. Hum. Mol. Genet. 2012 Jul;21:2889-98). In addition to the data presented in the literature, this alteration is expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Fanconi anemia complementation group O Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 18, 2019

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. 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, 29409816, 22451500, 27622768). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 27622768). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in an individual affected with ovarian cancer (PMID: 27622768). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with phenylalanine at codon 135 of the RAD51C protein (p.Cys135Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant also falls at the last nucleotide of exon 2 of the RAD51C coding sequence, which is part of the consensus splice site for this exon. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jan 02, 2024

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	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	35
DANN	Benign	0.81
DEOGEN2	Benign	0.23	T;T;T;T;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Uncertain	0.72	T
Sift4G	Uncertain	0.034	D;D;D;D;T
Polyphen		1.0	.;.;D;.;.
Vest4		0.82, 0.83
MutPred		0.73		.;Loss of ubiquitination at K131 (P = 0.1191);Loss of ubiquitination at K131 (P = 0.1191);.;.;
MVP		0.83
MPC		1.1
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.36		Position offset: -22
DS_DL_spliceai		0.92		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;