VCV000138870.29 - ClinVar

NM_058216.3(RAD51C):c.145+12T>G

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.

(18)

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.

Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(1); Likely benign(8)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_058216.3(RAD51C):c.145+12T>G

Variation ID: 138870 Accession: VCV000138870.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q22 17: 58692800 (GRCh38) [ NCBI UCSC ] 17: 56770161 (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 24, 2015	Feb 20, 2024	Jan 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_058216.3:c.145+12T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_002876.4:c.145+12T>G		intron variant
NC_000017.11:g.58692800T>G
NC_000017.10:g.56770161T>G
NG_023199.1:g.5199T>G
NG_047169.1:g.4280A>C
LRG_314:g.5199T>G
LRG_314t1:c.145+12T>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000017.11:58692799:T: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.

0.00020 (G)

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

Exome Aggregation Consortium (ExAC) 0.00013

The Genome Aggregation Database (gnomAD), exomes 0.00015

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Trans-Omics for Precision Medicine (TOPMed) 0.00022

The Genome Aggregation Database (gnomAD) 0.00024

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031

Links

ClinGen: CA293026 dbSNP: rs377297129 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
LOC130061310	-	-	-	GRCh38	-	42

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.
not specified	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV000127693.8
Fanconi anemia complementation group O	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jan 30, 2024	RCV000410695.17
Breast-ovarian cancer, familial, susceptibility to, 3	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Apr 27, 2017	RCV000411797.10
Hereditary cancer-predisposing syndrome	Likely benign (2)	criteria provided, multiple submitters, no conflicts	Nov 25, 2020	RCV000579441.5
Breast and/or ovarian cancer	Likely benign (1)	criteria provided, single submitter	Nov 5, 2021	RCV003149869.3
Malignant tumor of breast	Likely benign (1)	no assertion criteria provided	-	RCV001354401.4
not provided	Conflicting interpretations of pathogenicity (6)	no assertion criteria provided	Nov 2, 2014	RCV001195010.9

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.
Likely benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Fanconi anemia complementation group O Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001140709.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Fanconi anemia complementation group O Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001282773.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 3 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001285751.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 26740214 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Likely benign (Nov 25, 2020)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002531797.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022	Publications: PubMed (1) PubMed: 26740214
Likely benign (Nov 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV003837694.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868
Likely benign (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002551124.4 First in ClinVar: Jul 27, 2022 Last updated: Aug 18, 2023
Likely benign (Jan 30, 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: SCV002349813.3 First in ClinVar: Apr 08, 2022 Last updated: Feb 20, 2024
Benign (Feb 26, 2014)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000171272.11 First in ClinVar: Jun 23, 2014 Last updated: Feb 24, 2015	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Likely benign (Sep 03, 2015)	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: SCV000686326.2 First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022
Likely benign (Oct 25, 2016)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Fanconi anemia complementation group O Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000490071.2 First in ClinVar: Jan 09, 2017 Last updated: Dec 24, 2022
Likely benign (Oct 25, 2016)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 3 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000490072.2 First in ClinVar: Jan 09, 2017 Last updated: Dec 24, 2022
Uncertain significance (Nov 02, 2014)	no assertion criteria provided Method: curation	not provided Affected status: yes Allele origin: germline	Leiden Open Variation Database Accession: SCV001365244.1 First in ClinVar: Jun 28, 2020 Last updated: Jun 28, 2020	Comment: Curator: Arleen D. Auerbach. Submitter to LOVD: Christine Rappaport.
Likely benign (-)	no assertion criteria provided Method: clinical testing	Malignant tumor of breast Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001549011.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The RAD51C c.145+12T>G variant was not identified in the literature or in Cosmic, MutDB, and LOVD 3.0 databases. The variant was identified in dbSNP (ID: … (more) The RAD51C c.145+12T>G variant was not identified in the literature or in Cosmic, MutDB, and LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs377297129) â€šÃ„ÃºWith Likely benign alleleâ€šÃ„Ã¹, ClinVar (classified as benign by GeneDx and likely benign by Counsyl), Clinvitae (3x), and in control databases in 39 of 276870 chromosomes at a frequency of 0.0001 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017); seen in the following populations: African in 1 of 24024 chromosomes (frequency: 0.00004), Latino in 1 of 34412 chromosomes (frequency: 0.00003), and European Non-Finnish in 37 of 126410 chromosomes (frequency: 0.0003). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less) Number of individuals with the variant: 1
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001959215.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001905995.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001930004.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001977674.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001980054.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
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Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

The RAD51C c.145+12T>G variant was not identified in the literature or in Cosmic, MutDB, and LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs377297129) â€šÃ„ÃºWith Likely benign alleleâ€šÃ„Ã¹, ClinVar (classified as benign by GeneDx and likely benign by Counsyl), Clinvitae (3x), and in control databases in 39 of 276870 chromosomes at a frequency of 0.0001 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017); seen in the following populations: African in 1 of 24024 chromosomes (frequency: 0.00004), Latino in 1 of 34412 chromosomes (frequency: 0.00003), and European Non-Finnish in 37 of 126410 chromosomes (frequency: 0.0003). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Identification of six pathogenic RAD51C mutations via mutational screening of 1228 Danish individuals with increased risk of hereditary breast and/or ovarian cancer.	Jønson L	Breast cancer research and treatment	2016	PMID: 26740214
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868

Text-mined citations for rs377297129 ...

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.145+12T>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs377297129 ...