VCV000219853.18 - ClinVar

NM_058216.3(RAD51C):c.520A>G (p.Thr174Ala)

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.520A>G (p.Thr174Ala)

Variation ID: 219853 Accession: VCV000219853.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q22 17: 58696808 (GRCh38) [ NCBI UCSC ] 17: 56774169 (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	Dec 19, 2017	Jun 17, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_058216.3:c.520A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_478123.1:p.Thr174Ala	missense
NC_000017.11:g.58696808A>G
NC_000017.10:g.56774169A>G
NG_023199.1:g.9207A>G
NG_047169.1:g.272T>C
LRG_314:g.9207A>G
LRG_314t1:c.520A>G

... more HGVS ... less HGVS

Protein change

T174A

Other names

Canonical SPDI

NC_000017.11:58696807:A:G

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.

Links

ClinGen: CA349183 dbSNP: rs864622278 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 31, 2024	RCV000205015.9
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV000486898.6
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Jul 7, 2023	RCV000570805.4
Breast-ovarian cancer, familial, susceptibility to, 3 Fanconi anemia complementation group O	Uncertain significance (1)	criteria provided, single submitter	Apr 24, 2018	RCV000663210.1
Breast-ovarian cancer, familial, susceptibility to, 3	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Nov 21, 2023	RCV003316135.2

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 (Aug 15, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000567745.7 First in ClinVar: Apr 29, 2017 Last updated: Aug 24, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (Hauke et al., 2018); This variant is associated with the following publications: (PMID: 14704354, 29522266) (less)
Uncertain significance (Jan 31, 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: SCV000259955.8 First in ClinVar: Feb 02, 2016 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 29522266 Comment: This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 174 of the RAD51C protein (p.Thr174Ala). … (more) This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 174 of the RAD51C protein (p.Thr174Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29522266). ClinVar contains an entry for this variant (Variation ID: 219853). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD51C protein function with a negative predictive value of 80%. 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 (Apr 24, 2018)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Fanconi anemia complementation group O Breast-ovarian cancer, familial, susceptibility to, 3 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000786394.2 First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018
Uncertain significance (Jan 22, 2021)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV002046606.1 First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022	Publications: PubMed (1) PubMed: 29522266
Uncertain significance (Apr 05, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 3 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004019928.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Uncertain significance (Jul 07, 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: SCV000671923.6 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 29522266 Comment: The p.T174A variant (also known as c.520A>G), located in coding exon 3 of the RAD51C gene, results from an A to G substitution at nucleotide … (more) The p.T174A variant (also known as c.520A>G), located in coding exon 3 of the RAD51C gene, results from an A to G substitution at nucleotide position 520. The threonine at codon 174 is replaced by alanine, an amino acid with similar properties. This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med. 2018 04;7:1349-1358). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Nov 21, 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: SCV005053980.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (Hauke et al., 2018); This variant is associated with the following publications: (PMID: 14704354, 29522266)

Comment:

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 174 of the RAD51C protein (p.Thr174Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29522266). ClinVar contains an entry for this variant (Variation ID: 219853). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD51C protein function with a negative predictive value of 80%. 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.T174A variant (also known as c.520A>G), located in coding exon 3 of the RAD51C gene, results from an A to G substitution at nucleotide position 520. The threonine at codon 174 is replaced by alanine, an amino acid with similar properties. This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med. 2018 04;7:1349-1358). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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
Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer.	Hauke J	Cancer medicine	2018	PMID: 29522266

Text-mined citations for rs864622278 ...

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.520A>G (p.Thr174Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs864622278 ...