rs1060502601

chr17-58709883-AT-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_058216.3(RAD51C):c.732del(p.Ile244MetfsTer9) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000343 in 1,457,570 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RAD51C NM_058216.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 6.00

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-58709883-AT-A is Pathogenic according to our data. Variant chr17-58709883-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 409860.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.732del	p.Ile244MetfsTer9	frameshift_variant	5/9	ENST00000337432.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51C	ENST00000337432.9	c.732del	p.Ile244MetfsTer9	frameshift_variant	5/9	1	NM_058216.3	P2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1457570 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 725500

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: 0.00000451

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2016	This deletion of one nucleotide in RAD51C is denoted c.732delT at the cDNA level and p.Ile244MetfsX9 (I244MfsX9) at the protein level. The normal sequence, with the base that is deleted in braces, is GTAT[T]GCTT. The deletion causes a frameshift which changes an Isoleucine to a Methionine at codon 244, and creates a premature stop codon at position 9 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. RAD51C c.732delT, also known as 731delT using alternate nomenclature, has been observed in at least two individuals with a personal and family history of ovarian and/or breast cancer (Song 2015). Based on the currently available information, we consider this deletion to be a likely pathogenic variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Feb 10, 2023	PM4, PS4, PM2_SUP -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 15, 2020	This variant deletes 1 nucleotide in exon 5 of the RAD51C gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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 Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 20, 2022	The c.732delT pathogenic mutation, located in coding exon 5 of the RAD51C gene, results from a deletion of one nucleotide at nucleotide position 732, causing a translational frameshift with a predicted alternate stop codon (p.I244Mfs*9). This alteration has been reported in a cohort of women with invasive epithelial ovarian cancer (Song H et al. J. Clin. Oncol., 2015 Sep;33:2901-7). In addition to the clinical data presented in the literature, 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. -

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

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 06, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 05, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Mar 15, 2017

- -

Fanconi anemia complementation group O Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 10, 2023

This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 26261251, 26720728). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile244Metfs*9) 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 also known as c.731delT. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 409860). -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Dec 16, 2016

Variant summary: The RAD51C c.732delT (p.Ile244Metfs) variant results in a premature termination codon, predicted to cause a truncated or absent RAD51C protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/130846 control chromosomes at a frequency of 0.0000076, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625). The variant was reported in two affected individuals and one control individual from the literature (Song_2015, Norquist_2016). While this variant is predicted to be pathogenic, more clinical or functional data is needed to definitively classify this variant as pathogenic. Taken together, this variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1060502601; hg19: chr17-56787244;