17-58695182-C-T

Variant names:

• chr17-58695182-C-T
• rs387907159
• NM_058216.3:c.397C>T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_058216.3(RAD51C):​c.397C>T​(p.Gln133*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000096 in 1,458,216 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: RAD51C NM_058216.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 5.30

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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-58695182-C-T is Pathogenic according to our data. Variant chr17-58695182-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 31556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58695182-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51C	NM_058216.3	c.397C>T	p.Gln133*	stop_gained	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.397C>T	p.Gln133*	stop_gained	Exon 2 of 9	1	NM_058216.3	ENSP00000336701.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 247914 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134234

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: 0.00000895

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000960 AC: 14 AN: 1458216 Hom.: 0 Cov.: 31 AF XY: 0.00000828 AC XY: 6 AN XY: 724860

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: 0.0000108

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:4 Other:1

Sep 10, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2012

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RAD51C p.Gln133* variant was identified in 3 of 2450 proband chromosomes (frequency: 0.001) from individuals or families with ovarian or breast cancer and was not identified in 854 control chromosomes from healthy individuals (Loveday 2012, Thompson 2012). The variant was also identified in dbSNP (ID: rs387907159) as "With Pathogenic, Uncertain significance allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics and three other submitters) and LOVD 3.0, databases. The variant was identified in control databases in 1 of 242778 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 109692 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Gln133* variant leads to a premature stop codon at position 133, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the RAD51C gene are an established mechanism of disease in RAD51C associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Apr 06, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Jun 08, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Aug 25, 2011

Leiden Open Variation Database

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Ian Campbell. -

Jul 30, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29922827, 28888541, 22538716, 25470109, 21990120, 28281021, 23117857, 32885271, 33804961, 29625052, 34887416, 36451132, 31784482) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jan 15, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 2 of the RAD51C gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 1/247914 chromosomes 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 Pathogenic. -

May 12, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q133* pathogenic mutation (also known as c.397C>T), located in coding exon 2 of the RAD51C gene, results from a C to T substitution at nucleotide position 397. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This mutation has been identified in multiple breast and/or ovarian cancer families (Thompson ER et al. Hum. Mutat. 2012 Jan;33:95-9; Loveday C et al. Nat. Genet. 2012 Apr;44:475-6; author reply 476; Crawford B et al. Breast Cancer Res. Treat. 2017 Jun;163:383-390), and in a pancreatic cancer patient (Hu C et al. JAMA. 2018 06;319:2401-2409). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Fanconi anemia complementation group O Pathogenic:2

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln133*) in the RAD51C gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD51C are known to be pathogenic (PMID: 20400964, 21990120, 24800917, 29278735). This variant is present in population databases (rs387907159, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 21990120, 22538716). ClinVar contains an entry for this variant (Variation ID: 31556). For these reasons, this variant has been classified as Pathogenic. -

Jun 08, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Pathogenic:1

Nov 07, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RAD51C-related disorder Pathogenic:1

Aug 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RAD51C c.397C>T variant is predicted to result in premature protein termination (p.Gln133*). This variant has been reported in families and individuals with breast and/or ovarian cancer (Loveday et al. 2012. PubMed ID: 22538716; Thompson et al. 2012. PubMed ID: 21990120) and in an pancreatic cancer (eTable 3, Hu et al. 2018. PubMed ID: 29922827). This variant is reported in 0.00089% of alleles in individuals of European (non-Finnish) descent in gnomAD and is reported as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/31556/). Nonsense variants in RAD51C are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Mar 08, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RAD51C c.397C>T (p.Gln133X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 250888 control chromosomes (gnomAD). c.397C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (examples: Hu_2018, Loveday_2012, Thompson_2011) including a family in which an unaffected individual carried the variant suggesting reduced penetrance (Thompson_2011). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 29922827, 22538716, 21990120). ClinVar contains an entry for this variant (Variation ID: 31556). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.91	D
Vest4		0.92, 0.93, 0.69
ClinPred		1.0	D
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs387907159; hg19: chr17-56772543;