17-58732512-C-T

Position:

• chr17-58732512-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_058216.3(RAD51C):​c.994C>T​(p.Gln332Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,178 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RAD51C NM_058216.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.13

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]

LOC105371843 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.121 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-58732512-C-T is Pathogenic according to our data. Variant chr17-58732512-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 486279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD51C	NM_058216.3	c.994C>T	p.Gln332Ter	stop_gained	8/9	ENST00000337432.9	NP_478123.1
LOC105371843	XR_007065866.1	n.81-8087G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9	c.994C>T	p.Gln332Ter	stop_gained	8/9	1	NM_058216.3	ENSP00000336701	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461178 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726970

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 02, 2020	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 45 amino acids are lost including the nuclear localization signal (French 2003); Not observed in large population cohorts (Lek 2016); Observed in individuals with a personal or family history including ovarian and breast cancers (Kraus 2017); This variant is associated with the following publications: (PMID: 27616075) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 30, 2019	The variant is predicted to result in the loss of a functional protein. Not found in the total gnomAD dataset, and the data is high quality (0/281382 chr). -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 28, 2024	The p.Q332* variant (also known as c.994C>T), located in coding exon 8 of the RAD51C gene, results from a C to T substitution at nucleotide position 994. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This alteration occurs at the 3' terminus of theRAD51C gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 45 amino acids of the protein. However, premature stop codons are typically deleterious in nature and this variant is predicted to truncate the C-terminal region of the protein including the terminal end of the RECA domain (Magrane M et al. Database (Oxford) 2011). This alteration has been detected in an ovarian cancer patient diagnosed at age 63 who had a sister diagnosed with breast cancer at age 46 (Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102). This variant was also reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 25, 2020	This variant changes 1 nucleotide in exon 8 of the RAD51C gene, creating a translation stop signal. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a truncated protein lacking the nuclear localization signal (PMID: 12966089). To our knowledge, functional studies have not been reported for this variant. A functional study has reported that a truncation of the last 11 amino acids of the RAD51C protein partially reduced nuclear localization and ability to rescue sensitivity to mitomycin C treatment in RAD51C-deficient cell (PMID: 12966089). This variant has been reported in an individual affected with bilateral ovarian cancer (PMID: 27616075). 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:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 09, 2023

ClinVar contains an entry for this variant (Variation ID: 486279). 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 a region of the RAD51C protein in which other variant(s) (p.Ser353Hisfs*8) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 27616075). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln332*) in the RAD51C gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the RAD51C protein. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	D;D
Vest4		0.82
ClinPred		1.0	D
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs1555605074; hg19: chr17-56809873;