VCV000186362.26 - ClinVar

NM_058216.3(RAD51C):c.252G>T (p.Lys84Asn)

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.

(8)

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.252G>T (p.Lys84Asn)

Variation ID: 186362 Accession: VCV000186362.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q22 17: 58695037 (GRCh38) [ NCBI UCSC ] 17: 56772398 (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	Oct 8, 2024	Mar 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_058216.3:c.252G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_478123.1:p.Lys84Asn	missense
NM_002876.4:c.252G>T	NP_002867.1:p.Lys84Asn	missense
NR_103872.2:n.294G>T		non-coding transcript variant
NR_103873.1:n.220G>T		non-coding transcript variant
NC_000017.11:g.58695037G>T
NC_000017.10:g.56772398G>T
NG_023199.1:g.7436G>T
NG_047169.1:g.2043C>A
LRG_314:g.7436G>T
LRG_314t1:c.252G>T

... more HGVS ... less HGVS

Protein change

K84N

Other names

Canonical SPDI

NC_000017.11:58695036:G: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.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA194603 dbSNP: rs786202890 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	1857	2066

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.
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jul 14, 2022	RCV000165944.11
Fanconi anemia complementation group O	Uncertain significance (1)	criteria provided, single submitter	Jan 7, 2024	RCV000195928.12
not specified	Uncertain significance (1)	criteria provided, single submitter	Sep 7, 2017	RCV000781943.1
Breast-ovarian cancer, familial, susceptibility to, 3	Uncertain significance (2)	criteria provided, single submitter	Mar 24, 2024	RCV001535599.2
not provided	Uncertain significance (1)	criteria provided, single submitter	Nov 28, 2023	RCV001576516.4
RAD51C-related disorder	Uncertain significance (1)	no assertion criteria provided	Jan 5, 2024	RCV004535123.2

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 (Jul 14, 2022)	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: SCV000216700.7 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 26261251 Comment: The p.K84N variant (also known as c.252G>T), located in coding exon 2 of the RAD51C gene, results from a G to T substitution at nucleotide … (more) The p.K84N variant (also known as c.252G>T), located in coding exon 2 of the RAD51C gene, results from a G to T substitution at nucleotide position 252. The lysine at codon 84 is replaced by asparagine, an amino acid with similar properties. One study detected this alteration in 1/3429 patients with invasive epithelial ovarian cancer and 0/2772 control individuals (Song H et al. J. Clin. Oncol., 2015 Sep;33:2901-7). This amino acid position is 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 (Mar 24, 2024)	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: SCV005052680.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Uncertain significance (Nov 28, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001803722.2 First in ClinVar: Aug 21, 2021 Last updated: Sep 29, 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; This variant … (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; This variant is associated with the following publications: (PMID: 26261251, 35039523, 14704354) (less)
Uncertain significance (Sep 07, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000920377.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Publications: PubMed (1) PubMed: 26261251 Comment: Variant summary: The RAD51C c.252G>T (p.Lys84Asn) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant … (more) Variant summary: The RAD51C c.252G>T (p.Lys84Asn) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 126910 control chromosomes. The variant has been reported in one patient with ovarian cancer, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS. (less)
Uncertain significance (Jul 11, 2022)	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: SCV000912065.4 First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 26261251‚ 35039523 Comment: This missense variant replaces lysine with asparagine at codon 84 of the RAD51C protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces lysine with asparagine at codon 84 of the RAD51C protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 26261251) and in a tumor sample from an individual affected with familial breast cancer (PMID: 35039523). This variant has also been identified in 2/251460 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified 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: SCV000255187.11 First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 28492532‚ 26261251 Comment: This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 84 of the RAD51C protein (p.Lys84Asn). … (more) This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 84 of the RAD51C protein (p.Lys84Asn). This variant is present in population databases (rs786202890, gnomAD 0.002%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26261251). ClinVar contains an entry for this variant (Variation ID: 186362). 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 (Jan 05, 2024)	no assertion criteria provided Method: clinical testing	RAD51C-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004725230.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The RAD51C c.252G>T variant is predicted to result in the amino acid substitution p.Lys84Asn. This variant has been reported as a variant of uncertain significance … (more) The RAD51C c.252G>T variant is predicted to result in the amino acid substitution p.Lys84Asn. This variant has been reported as a variant of uncertain significance in a patient with ovarian cancer (Song et al. 2015. PubMed ID: 26261251). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant is interpreted as a variant of uncertain significance by multiple laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/186362/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
not provided (-)	no classification provided Method: phenotyping only	Breast-ovarian cancer, familial, susceptibility to, 3 Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV001749608.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021	Comment: Variant interpreted as Uncertain significance and reported on 11-11-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Uncertain significance and reported on 11-11-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Breast carcinoma (present) Indication for testing: Diagnostic Age: 60-69 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2019-11-11 Testing laboratory interpretation: Uncertain significance

Comment:

The p.K84N variant (also known as c.252G>T), located in coding exon 2 of the RAD51C gene, results from a G to T substitution at nucleotide position 252. The lysine at codon 84 is replaced by asparagine, an amino acid with similar properties. One study detected this alteration in 1/3429 patients with invasive epithelial ovarian cancer and 0/2772 control individuals (Song H et al. J. Clin. Oncol., 2015 Sep;33:2901-7). This amino acid position is 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.

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; This variant is associated with the following publications: (PMID: 26261251, 35039523, 14704354)

Comment:

Variant summary: The RAD51C c.252G>T (p.Lys84Asn) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 126910 control chromosomes. The variant has been reported in one patient with ovarian cancer, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.

Comment:

This missense variant replaces lysine with asparagine at codon 84 of the RAD51C protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 26261251) and in a tumor sample from an individual affected with familial breast cancer (PMID: 35039523). This variant has also been identified in 2/251460 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 84 of the RAD51C protein (p.Lys84Asn). This variant is present in population databases (rs786202890, gnomAD 0.002%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26261251). ClinVar contains an entry for this variant (Variation ID: 186362). 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 RAD51C c.252G>T variant is predicted to result in the amino acid substitution p.Lys84Asn. This variant has been reported as a variant of uncertain significance in a patient with ovarian cancer (Song et al. 2015. PubMed ID: 26261251). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant is interpreted as a variant of uncertain significance by multiple laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/186362/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Comment:

Variant interpreted as Uncertain significance and reported on 11-11-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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
Integration of tumour sequencing and case-control data to assess pathogenicity of RAD51C missense variants in familial breast cancer.	Lim BWX	NPJ breast cancer	2022	PMID: 35039523
Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population.	Song H	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2015	PMID: 26261251

Text-mined citations for rs786202890 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_058216.3(RAD51C):c.252G>T (p.Lys84Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs786202890 ...