VCV000480497.24 - ClinVar

NM_058216.3(RAD51C):c.572-1G>C

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.

Pathogenic/Likely pathogenic

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.572-1G>C

Variation ID: 480497 Accession: VCV000480497.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q22 17: 58703195 (GRCh38) [ NCBI UCSC ] 17: 56780556 (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	Feb 19, 2018	May 1, 2024	Jan 3, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_058216.3:c.572-1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NC_000017.11:g.58703195G>C
NC_000017.10:g.56780556G>C
NG_023199.1:g.15594G>C
NG_156533.1:g.71G>C
LRG_314:g.15594G>C
LRG_314t1:c.572-1G>C

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000017.11:58703194:G:C

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: CA400348971 dbSNP: rs1413872299 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	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 31, 2023	RCV000562532.12
Breast-ovarian cancer, familial, susceptibility to, 3	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 3, 2024	RCV000755025.5
Fanconi anemia complementation group O	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 17, 2023	RCV001068269.9

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.
Pathogenic (Oct 24, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 3 Affected status: yes Allele origin: germline	Department of Molecular Diagnostics, Institute of Oncology Ljubljana Accession: SCV000882845.1 First in ClinVar: Feb 17, 2019 Last updated: Feb 17, 2019
Pathogenic (Feb 20, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group O Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001370199.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Pathogenic (Dec 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Breast-ovarian cancer, familial, susceptibility to, 3 Affected status: no Allele origin: germline	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV002762840.2 First in ClinVar: Dec 17, 2022 Last updated: Feb 25, 2023	Comment: PVS1_STR, PS4_SUP, PM2_SUP
Likely pathogenic (Feb 22, 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: SCV004208016.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Likely pathogenic (Mar 15, 2023)	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: SCV000691254.5 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 26261251‚ 27908594‚ 30949688‚ 35740625 Comment: This variant causes a G>C nucleotide substitution at the -1 position of intron 3 of the RAD51C gene. Splice site prediction tools predict that this … (more) This variant causes a G>C nucleotide substitution at the -1 position of intron 3 of the RAD51C gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A minigene splicing assay has shown that this variant resulted in the out-of-frame skipping of exon 4 (PMID: 35740625). This variant has been reported in an individual affected with ovarian cancer (PMID: 26261251). Different substitutions in canonical splice site positions at this acceptor site, c.572-1G>T and c.572-2A>G, have been reported in one individual each affected with breast cancer or ovarian cancer (PMID: 27908594, 30949688). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51C function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Likely pathogenic (Dec 17, 2023)	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: SCV001233368.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024	Publications: PubMed (8) PubMed: 16199547‚ 20400964‚ 21990120‚ 24800917‚ 29278735‚ 26261251‚ 28888541‚ 32107557 Comment: This sequence change affects an acceptor splice site in intron 3 of the RAD51C gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more) This sequence change affects an acceptor splice site in intron 3 of the RAD51C gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RAD51C are known to be pathogenic (PMID: 20400964, 21990120, 24800917, 29278735). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast or ovarian cancer (PMID: 26261251, 28888541, 32107557). ClinVar contains an entry for this variant (Variation ID: 480497). Studies have shown that disruption of this splice site is associated with inconclusive levels of altered splicing (Invitae). 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. (less)
Likely pathogenic (Jan 03, 2024)	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: SCV004931720.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either … (more) This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. (less)
Likely pathogenic (Aug 31, 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: SCV000663772.7 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Comment: The c.572-1G>C intronic variant results from a G to C substitution one nucleotide before coding exon 4 of the RAD51C gene. This variant is considered … (more) The c.572-1G>C intronic variant results from a G to C substitution one nucleotide before coding exon 4 of the RAD51C gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. (less)

Comment:

This variant causes a G>C nucleotide substitution at the -1 position of intron 3 of the RAD51C gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A minigene splicing assay has shown that this variant resulted in the out-of-frame skipping of exon 4 (PMID: 35740625). This variant has been reported in an individual affected with ovarian cancer (PMID: 26261251). Different substitutions in canonical splice site positions at this acceptor site, c.572-1G>T and c.572-2A>G, have been reported in one individual each affected with breast cancer or ovarian cancer (PMID: 27908594, 30949688). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51C function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.

Comment:

This sequence change affects an acceptor splice site in intron 3 of the RAD51C gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RAD51C are known to be pathogenic (PMID: 20400964, 21990120, 24800917, 29278735). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast or ovarian cancer (PMID: 26261251, 28888541, 32107557). ClinVar contains an entry for this variant (Variation ID: 480497). Studies have shown that disruption of this splice site is associated with inconclusive levels of altered splicing (Invitae). 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.

Comment:

This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.

Comment:

The c.572-1G>C intronic variant results from a G to C substitution one nucleotide before coding exon 4 of the RAD51C gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.

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
Minigene Splicing Assays Identify 20 Spliceogenic Variants of the Breast/Ovarian Cancer Susceptibility Gene RAD51C.	Sanoguera-Miralles L	Cancers	2022	PMID: 35740625
Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in RAD51C and RAD51D.	Yang X	Journal of the National Cancer Institute	2020	PMID: 32107557
Combined Tumor Sequencing and Case-Control Analyses of RAD51C in Breast Cancer.	Li N	Journal of the National Cancer Institute	2019	PMID: 30949688
Expanding the FANCO/RAD51C associated phenotype: Cleft lip and palate and lobar holoprosencephaly, two rare findings in Fanconi anemia.	Jacquinet A	European journal of medical genetics	2018	PMID: 29278735
Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls.	Lilyquist J	Gynecologic oncology	2017	PMID: 28888541
Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial.	Swisher EM	The Lancet. Oncology	2017	PMID: 27908594
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
Deleterious RAD51C germline mutations rarely predispose to breast and ovarian cancer in Pakistan.	Rashid MU	Breast cancer research and treatment	2014	PMID: 24800917
Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients.	Thompson ER	Human mutation	2012	PMID: 21990120
Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene.	Meindl A	Nature genetics	2010	PMID: 20400964
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
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Text-mined citations for rs1413872299 ...

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.572-1G>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1413872299 ...