NM_058216.3(RAD51C):c.706-2A>G AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 8, 2024
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:: RCV000116178.17

Allele description [Variation Report for NM_058216.3(RAD51C):c.706-2A>G]

NM_058216.3(RAD51C):c.706-2A>G

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

17q22

Genomic location:

Preferred name:

NM_058216.3(RAD51C):c.706-2A>G

Other names:

IVS4-2A>G

HGVS:

NC_000017.11:g.58709857A>G
NG_023199.1:g.22256A>G
NM_058216.3:c.706-2A>GMANE SELECT
LRG_314t1:c.706-2A>G
LRG_314:g.22256A>G
NC_000017.10:g.56787218A>G
NM_058216.1:c.706-2A>G
NM_058216.2:c.706-2A>G

Links:

dbSNP: rs587780259

NCBI 1000 Genomes Browser:

rs587780259

Molecular consequence:

NM_058216.3:c.706-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

Functional consequence:

effect on RNA splicing [Variation Ontology: 0362]

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
SCV000186640	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 29, 2022)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 20400964, 21990120, 24139550, 24549055, 24800917, 25452441, 26261251, 26681312, 28123851, 28152038, 28905878, 29053726, 29255180 Citation Link,
SCV000686377	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 22006311, 22538716, 24139550, 25452441, 26261251, 26681312, 28905878, 29053726, 29255180, 33333735, 25741868
SCV002530006	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Jan 25, 2022)	germline	curation	PubMed (4) [See all records that cite these PMIDs] 22006311, 24139550, 25452441, 28905878 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000186640

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 29, 2022)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

Citation Link,

SCV000686377

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 8, 2024)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV002530006

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Pathogenic
(Jan 25, 2022)

germline

curation

PubMed (4)
[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

Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene.

Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, Niederacher D, Freund M, Lichtner P, Hartmann L, Schaal H, Ramser J, Honisch E, Kubisch C, Wichmann HE, Kast K, Deissler H, Engel C, Müller-Myhsok B, Neveling K, Kiechle M, Mathew CG, Schindler D, et al.

Nat Genet. 2010 May;42(5):410-4. doi: 10.1038/ng.569. Epub 2010 Apr 18.

PubMed [citation]

PMID:: 20400964

Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients.

Thompson ER, Boyle SE, Johnson J, Ryland GL, Sawyer S, Choong DY, kConFab, Chenevix-Trench G, Trainer AH, Lindeman GJ, Mitchell G, James PA, Campbell IG.

Hum Mutat. 2012 Jan;33(1):95-9. doi: 10.1002/humu.21625. Epub 2011 Nov 4.

PubMed [citation]

PMID:: 21990120

See all PubMed Citations (17)

Details of each submission

From Ambry Genetics, SCV000186640.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

The c.706-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 5 of the RAD51C gene. This alteration has been reported in multiple individuals with personal and/or family history of breast and/or ovarian cancer (Meindl A et al. Nat. Genet. 2010 May;42:410-4; Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7; Loveday C et al. Nat. Genet. 2012 May;44:475-6; Golmard L et al. BMC Cancer. 2013 Oct;13:484; Castéra L et al. Eur. J. Hum. Genet. 2014 Nov;22:1305-13; Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32; Kotoula V et al. Am J Cancer Res. 2017 Jan;7:98-114; Harter P et al. PLoS ONE. 2017 Oct;12:e0186043; Golmard L et al. Eur. J. Hum. Genet. 2017 12;25:1345-1353). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA analyses have shown that this mutation leads to skipping of exon 5, resulting in an in-frame deletion of 44 amino acid residues including the Walker B box in the functionally important RecA domain (Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7; Golmard L et al. BMC Cancer. 2013 Oct;13:484; Davy G et al. Eur. J. Hum. Genet. 2017 10;25:1147-1154; Ambry internal data). Based on the supporting evidence, 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, SCV000686377.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This variant causes an A to G nucleotide substitution at the -2 position of intron 4 of the RAD51C gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. RNA studies have shown that this variant causes the skipping of exon 5, resulting in an in-frame deletion of 44 amino acids including the Walker B motif in the ATP-binding domain of the RAD51C protein (PMID: 22006311, 24139550, 28905878, 33333735). This variant is expected to cause a defect in RAD51C protein function. This variant has been reported in many individuals affected with breast or ovarian cancer (PMID: 22006311, 22538716, 24139550, 25452441, 26261251, 26681312, 29053726, 29255180). This variant has been identified in 6/282746 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, SCV002530006.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (4)

#	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: Nov 3, 2024

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