NM_058216.3(RAD51C):c.93del (p.Phe32fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 20, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000160936.14

Allele description [Variation Report for NM_058216.3(RAD51C):c.93del (p.Phe32fs)]

NM_058216.3(RAD51C):c.93del (p.Phe32fs)

Gene:

RAD51C:RAD51 paralog C [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

17q22

Genomic location:

Preferred name:

NM_058216.3(RAD51C):c.93del (p.Phe32fs)

HGVS:

NC_000017.11:g.58692736del
NG_023199.1:g.5135del
NG_047169.1:g.4347del
NM_002876.4:c.93del
NM_058216.3:c.93delMANE SELECT
NP_002867.1:p.Phe32fs
NP_478123.1:p.Phe32fs
LRG_314t1:c.93del
LRG_314:g.5135del
NC_000017.10:g.56770094del
NC_000017.10:g.56770097del
NC_000017.10:g.56770097delG
NM_002876.2:c.93delG
NM_058216.1:c.93del
NM_058216.1:c.93delG
NM_058216.2:c.93delG
NR_103872.2:n.135del
p.F32SfsX8
p.G31GFS*9

Protein change:

F32fs

Links:

OMIM: 602774.0007; dbSNP: rs730881942

NCBI 1000 Genomes Browser:

rs730881942

Molecular consequence:

NM_002876.4:c.93del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_058216.3:c.93del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_103872.2:n.135del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000215256	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Mar 31, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21616938, 23176254, 26681312, 27433846, 28802053 Citation Link,
SCV000691291	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 20, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21616938, 27433846, 25741868
SCV002530035	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Jan 27, 2022)	germline	curation	PubMed (5) [See all records that cite these PMIDs] 21616938, 26681312, 27433846, 23176254, 20400964 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000215256

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Mar 31, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV000691291

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 20, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002530035

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Pathogenic
(Jan 27, 2022)

germline

curation

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Gene-panel testing of breast and ovarian cancer patients identifies a recurrent RAD51C duplication.

Pelttari LM, Shimelis H, Toiminen H, Kvist A, Törngren T, Borg Å, Blomqvist C, Bützow R, Couch F, Aittomäki K, Nevanlinna H.

Clin Genet. 2018 Mar;93(3):595-602. doi: 10.1111/cge.13123. Epub 2018 Jan 12.

PubMed [citation]

PMID:: 28802053

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000215256.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The c.93delG pathogenic mutation, located in coding exon 1 of the RAD51C gene, results from a deletion of one nucleotide at position 93, causing a translational frameshift with a predicted alternate stop codon (p.F32Sfs*8). This mutation has been identified in a Finnish breast/ovarian cancer kindred as well as multiple ovarian cancer only families to date (Pelttari LM et al. Hum. Mol. Genet. 2011 Aug;20:3278-88). This same group did not find the c.93delG alteration in a group of 1083 prostate cancer patients and 802 colorectal cancer patients, leading the authors to conclude that this mutation does not predispose to prostate or colorectal cancer (Pelttari LM et al. BMC Cancer. 2012;12:552). In a different prostate cancer cohort, this alteration was identified in 1/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53). In addition, this alteration was identified in 2/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 08;18:823-32). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000691291.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant deletes 1 nucleotide in exon 1 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 been reported in an individual affected with familial ovarian cancer and another individual affected breast cancer with multiple relatives affected with breast or ovarian cancer (PMID: 21616938). This variant has also been observed in an individual with prostate cancer (PMID: 27433846). This variant has been identified in 13/282860 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002530035.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (5)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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