VCV000409837.25 - ClinVar

NM_058216.3(RAD51C):c.34C>T (p.Arg12Trp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_058216.3(RAD51C):c.34C>T (p.Arg12Trp)

Variation ID: 409837 Accession: VCV000409837.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q22 17: 58692677 (GRCh38) [ NCBI UCSC ] 17: 56770038 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 29, 2017	Sep 16, 2024	Jan 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_058216.3:c.34C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_478123.1:p.Arg12Trp	missense
NM_002876.4:c.34C>T	NP_002867.1:p.Arg12Trp	missense
NR_103872.2:n.76C>T		non-coding transcript variant
NR_103873.1:n.105C>T		non-coding transcript variant
NC_000017.11:g.58692677C>T
NC_000017.10:g.56770038C>T
NG_023199.1:g.5076C>T
NG_047169.1:g.4403G>A
LRG_314:g.5076C>T
LRG_314t1:c.34C>T

... more HGVS ... less HGVS

Protein change

R12W

Other names

Canonical SPDI

NC_000017.11:58692676:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00004

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

Links

ClinGen: CA8677126 dbSNP: rs28910276 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RAD51C		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1858	2067

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Fanconi anemia complementation group O	Uncertain significance (1)	criteria provided, single submitter	Jan 7, 2024	RCV000464422.9
not provided	Uncertain significance (1)	criteria provided, single submitter	Jan 26, 2024	RCV000485483.5
Hereditary cancer-predisposing syndrome	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	May 23, 2023	RCV000574346.10
Breast-ovarian cancer, familial, susceptibility to, 3	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Nov 18, 2023	RCV001526803.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Apr 24, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000686345.3 First in ClinVar: Feb 19, 2018 Last updated: Jun 22, 2020
Uncertain significance (Jun 10, 2021)	criteria provided, single submitter (St. Jude Assertion Criteria 2020) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 3 Affected status: unknown Allele origin: germline	St. Jude Molecular Pathology, St. Jude Children's Research Hospital Accession: SCV001737435.2 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Comment: The RAD51C c.34C>T (p.Arg12Trp) missense change has a maximum subpopulation frequency of 0.0080% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/17-56770038-C-T?dataset=gnomad_r2_1). In silico tools are not in agreement about … (more) The RAD51C c.34C>T (p.Arg12Trp) missense change has a maximum subpopulation frequency of 0.0080% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/17-56770038-C-T?dataset=gnomad_r2_1). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. This variant is present 2X in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (BS2_Supporting; https://whi.color.com/variant/17-56770038-C-T). This variant was investigated in a case control study of 81 patients with head and neck cancer and 156 healthy control individuals (PMID: 24631219) and a study of 132 breast cancer cases and 189 healthy control individuals (PMID: 31905201), however it was not observed in any cases or controls. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BS2_Supporting. (less)
Uncertain significance (Feb 07, 2022)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002531810.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The RAD51C c.34C>T (p.R12W) variant has not been reported in the literature to our knowledge. This variant was observed in 2/24964 chromosomes in the African/African … (more) The RAD51C c.34C>T (p.R12W) variant has not been reported in the literature to our knowledge. This variant was observed in 2/24964 chromosomes in the African/African American population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 409837). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Based on the current evidence available, this variant is interpreted as a variant of uncertain significance. (less)
Uncertain significance (Jan 07, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Fanconi anemia complementation group O Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000550187.8 First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 21537932 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 12 of the RAD51C protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 12 of the RAD51C protein (p.Arg12Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer (PMID: 21537932). ClinVar contains an entry for this variant (Variation ID: 409837). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (May 23, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000671901.6 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 21537932‚ 24631219 Comment: The p.R12W variant (also known as c.34C>T), located in coding exon 1 of the RAD51C gene, results from a C to T substitution at nucleotide … (more) The p.R12W variant (also known as c.34C>T), located in coding exon 1 of the RAD51C gene, results from a C to T substitution at nucleotide position 34. The arginine at codon 12 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Nov 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 3 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004207958.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Uncertain significance (Jan 26, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000567112.8 First in ClinVar: Apr 29, 2017 Last updated: Sep 16, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: moderately deficient homologous recombination activity and impaired protein-protein interactions (PMID: 36099300); This variant is associated with the following publications: (PMID: 24631219, 21537932, 36099300) (less)

Comment:

The RAD51C c.34C>T (p.Arg12Trp) missense change has a maximum subpopulation frequency of 0.0080% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/17-56770038-C-T?dataset=gnomad_r2_1). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. This variant is present 2X in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (BS2_Supporting; https://whi.color.com/variant/17-56770038-C-T). This variant was investigated in a case control study of 81 patients with head and neck cancer and 156 healthy control individuals (PMID: 24631219) and a study of 132 breast cancer cases and 189 healthy control individuals (PMID: 31905201), however it was not observed in any cases or controls. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BS2_Supporting.

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 12 of the RAD51C protein (p.Arg12Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer (PMID: 21537932). ClinVar contains an entry for this variant (Variation ID: 409837). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The p.R12W variant (also known as c.34C>T), located in coding exon 1 of the RAD51C gene, results from a C to T substitution at nucleotide position 34. The arginine at codon 12 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: moderately deficient homologous recombination activity and impaired protein-protein interactions (PMID: 36099300); This variant is associated with the following publications: (PMID: 24631219, 21537932, 36099300)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Rad51C: a novel suppressor gene modulates the risk of head and neck cancer.	Gresner P	Mutation research	2014	PMID: 24631219
A HRM-based screening method detects RAD51C germ-line deleterious mutations in Spanish breast and ovarian cancer families.	Romero A	Breast cancer research and treatment	2011	PMID: 21537932

Text-mined citations for rs28910276 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_058216.3(RAD51C):c.34C>T (p.Arg12Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28910276 ...