NM_058216.3(RAD51C):c.404G>T (p.Cys135Phe) AND Fanconi anemia complementation group O

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 18, 2019
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001212223.7

Allele description [Variation Report for NM_058216.3(RAD51C):c.404G>T (p.Cys135Phe)]

NM_058216.3(RAD51C):c.404G>T (p.Cys135Phe)

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.404G>T (p.Cys135Phe)

HGVS:

NC_000017.11:g.58695189G>T
NG_023199.1:g.7588G>T
NG_047169.1:g.1891C>A
NM_002876.4:c.404G>T
NM_058216.3:c.404G>TMANE SELECT
NP_002867.1:p.Trp135Leu
NP_478123.1:p.Cys135Phe
LRG_314t1:c.404G>T
LRG_314:g.7588G>T
NC_000017.10:g.56772550G>T
NM_058216.1:c.404G>T
NM_058216.2:c.404G>T
NR_103872.2:n.446G>T
NR_103873.1:n.372G>T

Protein change:

C135F

Links:

dbSNP: rs767796996

NCBI 1000 Genomes Browser:

rs767796996

Molecular consequence:

NM_002876.4:c.404G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_058216.3:c.404G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_103872.2:n.446G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_103873.1:n.372G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Fanconi anemia complementation group O
Identifiers:: MONDO: MONDO:0013248; MedGen: C3150653; Orphanet: 84; OMIM: 613390

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001383800	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 18, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22451500, 17576681, 9536098, 27622768, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001383800

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 18, 2019)

germline

clinical testing

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

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

Citations

PubMed

Predominance of pathogenic missense variants in the RAD51C gene occurring in breast and ovarian cancer families.

Osorio A, Endt D, Fernández F, Eirich K, de la Hoya M, Schmutzler R, Caldés T, Meindl A, Schindler D, Benitez J.

Hum Mol Genet. 2012 Jul 1;21(13):2889-98. doi: 10.1093/hmg/dds115. Epub 2012 Mar 26.

PubMed [citation]

PMID:: 22451500

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001383800.5

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

Description

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 the c.404G nucleotide in the RAD51C gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 22451500,¬†29409816, 22451500, 27622768). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 27622768). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in an individual affected with ovarian cancer (PMID: 27622768). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with phenylalanine at codon 135 of the RAD51C protein (p.Cys135Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant also falls at the last nucleotide of exon 2 of the RAD51C coding sequence, which is part of the consensus splice site for this exon.

#	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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