VCV000041540.90 - ClinVar

NM_000059.4(BRCA2):c.10234A>G (p.Ile3412Val)

Germline

Top reviewed classifications are shown here.

Submission summary:

44 submissions

43 submitters

11 conditions

Reviewed by expert panel

Benign

Jan 2015 by Evidence-based…

for Breast-ovarian cancer, familial 2

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000059.4(BRCA2):c.10234A>G (p.Ile3412Val)

Variation ID: 41540 Accession: VCV000041540.90

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q13.1 13: 32398747 (GRCh38) [ NCBI UCSC ] 13: 32972884 (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 12, 2013	Sep 29, 2024	Jan 12, 2015

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.10234A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Ile3412Val	missense
NC_000013.11:g.32398747A>G
NC_000013.10:g.32972884A>G
NG_012772.3:g.88268A>G
LRG_293:g.88268A>G
LRG_293t1:c.10234A>G	LRG_293p1:p.Ile3412Val
	NP_000050.2:p.Ile3412Val
U43746.1:n.10462A>G

... more HGVS ... less HGVS

Protein change

I3412V

Other names

10462 A>G
NP_000050.3:p.Ile3412Val
10462A>G

Canonical SPDI

NC_000013.11:32398746: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.

0.04493 (G)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.03729

The Genome Aggregation Database (gnomAD) 0.03864

Trans-Omics for Precision Medicine (TOPMed) 0.04474

Exome Aggregation Consortium (ExAC) 0.02266

The Genome Aggregation Database (gnomAD), exomes 0.02331

1000 Genomes Project 0.04493

1000 Genomes Project 30x 0.04653

Links

ClinGen: CA010536 dbSNP: rs1801426 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.
BRCA2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	18985	19144

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 provided	Benign (5)	criteria provided, multiple submitters, no conflicts	Nov 29, 2023	RCV000034426.31
Breast-ovarian cancer, familial, susceptibility to, 2	Benign (12)	reviewed by expert panel	Jan 12, 2015	RCV000112853.27
not specified	Benign/Likely benign (11)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV000120373.44
Hereditary cancer-predisposing syndrome	Benign (5)	criteria provided, multiple submitters, no conflicts	Mar 23, 2020	RCV000130982.15
Breast neoplasm	Uncertain significance (1)	criteria provided, single submitter	-	RCV000414645.9
Familial cancer of breast	Benign (2)	criteria provided, single submitter	Feb 23, 2017	RCV000460200.10
Hereditary breast ovarian cancer syndrome	Benign (4)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000267039.23
Fanconi anemia complementation group D1	Benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV000361728.13
Malignant tumor of breast	Benign (1)	no assertion criteria provided	-	RCV001353766.10
Breast and/or ovarian cancer	Benign (1)	criteria provided, single submitter	Jul 10, 2015	RCV000769708.10
Breast-ovarian cancer, familial, susceptibility to, 2 Familial cancer of breast Fanconi anemia complementation group D1 Glioma susceptibility 3 Malignant tumor of prostate Medulloblastoma Pancreatic cancer, susceptibility to, 2 Wilms tumor 1	Benign (1)	criteria provided, single submitter	May 17, 2022	RCV002477053.8
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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.
Benign (Jan 12, 2015)	reviewed by expert panel (ENIGMA BRCA1/2 Classification Criteria (2015)) Method: curation	Breast-ovarian cancer, familial 2 Affected status: unknown Allele origin: germline	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Accession: SCV000245314.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015	Comment: Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.02972 (Asian), 0.126 (African), derived from 1000 genomes (2012-04-30).
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000301751.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Jan 06, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Vantari Genetics Accession: SCV000267029.1 First in ClinVar: Apr 13, 2016 Last updated: Apr 13, 2016
Uncertain significance (-)	criteria provided, single submitter (Carraro et al. (PLoS One. 2013)) Method: research	Breast Cancer Affected status: yes Allele origin: germline	A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center Accession: SCV000492484.1 First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017	Publications: PubMed (2) PubMed: 23469205‚ 24884479
Benign (Jun 28, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000511440.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017
Benign (Mar 28, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000538466.1 First in ClinVar: Oct 22, 2016 Last updated: Oct 22, 2016	Comment: Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more) Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency (less) Method: Genome/Exome Filtration
Benign (Feb 23, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast (Autosomal dominant inheritance) Affected status: no Allele origin: germline	Baylor Genetics Accession: SCV000541023.1 First in ClinVar: Apr 17, 2017 Last updated: Apr 17, 2017
Benign (Mar 19, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000202310.7 First in ClinVar: Jan 29, 2015 Last updated: Sep 22, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRCA2 Number of individuals with the variant: 25 Sex: mixed
Benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Fanconi anemia complementation group D1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000383811.3 First in ClinVar: Dec 06, 2016 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
Benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000383812.3 First in ClinVar: Dec 06, 2016 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. (less)
Benign (Jun 15, 2020)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV001470191.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021
Benign (Mar 23, 2020)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002533200.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Benign (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004016847.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
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: SCV002551863.4 First in ClinVar: Jul 30, 2022 Last updated: Aug 18, 2023
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000560423.8 First in ClinVar: Feb 04, 2017 Last updated: Feb 28, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005236566.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Nov 03, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Michigan Medical Genetics Laboratories, University of Michigan Accession: SCV000196032.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015	Tissue: Blood
Benign (Nov 05, 2014)	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: SCV000537369.1 First in ClinVar: Mar 24, 2017 Last updated: Mar 24, 2017
Benign (Apr 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000586996.1 First in ClinVar: Oct 22, 2016 Last updated: Oct 22, 2016
Benign (Oct 09, 2014)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743531.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (Sep 21, 2015)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000744797.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (Jul 10, 2015)	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 Study: Canadian Open Genetics Repository Accession: SCV000901127.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019
Benign (Apr 19, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State Accession: SCV002025890.2 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: DOI: 10.3389/fgene.2022.834265 DOI: 10.3389/fgene.2022.834265 Number of individuals with the variant: 138 Geographic origin: South Africa
Benign (Nov 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	Genetics Program, Instituto Nacional de Cancer Accession: SCV002515173.1 First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022	Publications: PubMed (1) PubMed: 36329109 Geographic origin: Brazil
Benign (Jan 13, 2014)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000494298.2 First in ClinVar: Feb 04, 2017 Last updated: Dec 11, 2022	Publications: PubMed (2) PubMed: 21356067‚ 15317758
Benign (Jan 02, 2014)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: literature only	Breast-ovarian cancer, familial 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000154054.2 First in ClinVar: Jun 09, 2014 Last updated: Dec 24, 2022	Publications: PubMed (5) PubMed: 22703879‚ 17341484‚ 21356067‚ 9150152‚ 11389159
Benign (May 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Medulloblastoma Familial prostate cancer Wilms tumor 1 Fanconi anemia complementation group D1 Breast-ovarian cancer, familial, susceptibility to, 2 Glioma susceptibility 3 Pancreatic cancer, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000575738.2 First in ClinVar: Sep 29, 2015 Last updated: Dec 31, 2022
Benign (Nov 29, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000602768.10 First in ClinVar: Sep 28, 2017 Last updated: Feb 20, 2024
Benign (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004846283.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Number of individuals with the variant: 3237
Benign (Nov 19, 2014)	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: SCV000185899.7 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (Mar 14, 2011)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: not provided Allele origin: germline	Sharing Clinical Reports Project (SCRP) Accession: SCV000189292.1 First in ClinVar: Sep 27, 2014 Last updated: Sep 27, 2014
Benign (-)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733345.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001798663.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Benign (Mar 02, 2020)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	BRCAlab, Lund University Accession: SCV004243898.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024
no known pathogenicity (Jul 13, 2012)	no assertion criteria provided Method: research	not provided Affected status: no Allele origin: germline	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000043241.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013	Publications: PubMed (1) PubMed: 22703879 Comment: Converted during submission to Benign. Number of individuals with the variant: 9 Comment on evidence: The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
Uncertain significance (Feb 05, 2013)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: yes Allele origin: germline	Breast Cancer Information Core (BIC) (BRCA2) Accession: SCV000145770.1 First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014	Observation 1: Number of individuals with the variant: 52 Observation 2: Number of individuals with the variant: 9 Geographic origin: African American Observation 3: Number of individuals with the variant: 2 Geographic origin: Asian Observation 4: Number of individuals with the variant: 1 Geographic origin: Austria Observation 5: Number of individuals with the variant: 2 Geographic origin: Brazil Observation 6: Number of individuals with the variant: 1 Geographic origin: Central/Eastern European Observation 7: Number of individuals with the variant: 7 Geographic origin: Latin American, Caribbean Observation 8: Number of individuals with the variant: 4 Geographic origin: Western European Observation 9: Number of individuals with the variant: 1 Geographic origin: Western European, African American, Pakistan Observation 10: Number of individuals with the variant: 1 Geographic origin: Western European, Latin American, Caribbean Observation 11: Number of individuals with the variant: 1 Geographic origin: Western, Central/Eastern European Observation 12: Number of individuals with the variant: 10 Ethnicity/Population group: African American Observation 13: Number of individuals with the variant: 2 Ethnicity/Population group: African American, Native American Observation 14: Number of individuals with the variant: 2 Ethnicity/Population group: Asian Observation 15: Number of individuals with the variant: 1 Ethnicity/Population group: Asian, Philippine Observation 16: Number of individuals with the variant: 1 Ethnicity/Population group: Austrian, African, Am, Indian Observation 17: Number of individuals with the variant: 1 Ethnicity/Population group: Caucasian Geographic origin: Czech Republic Observation 18: Number of individuals with the variant: 1 Ethnicity/Population group: Caucasian Geographic origin: Denmark Observation 19: Number of individuals with the variant: 1 Ethnicity/Population group: Caucasian Geographic origin: Sicilian Observation 20: Number of individuals with the variant: 1 Ethnicity/Population group: Chinese Geographic origin: Malaysia Observation 21: Number of individuals with the variant: 2 Ethnicity/Population group: Irish, Scottish Observation 22: Number of individuals with the variant: 6 Ethnicity/Population group: Latin American, Caribbean Observation 23: Number of individuals with the variant: 2 Ethnicity/Population group: Native American, African American Observation 24: Number of individuals with the variant: 1 Ethnicity/Population group: Near Eastern Mid Eastern Latin American, Caribb Observation 25: Number of individuals with the variant: 2 Ethnicity/Population group: Western European Observation 26: Number of individuals with the variant: 1 Ethnicity/Population group: Western European, Native American
Benign (Jan 31, 2014)	no assertion criteria provided Method: research	not specified Affected status: yes Allele origin: germline	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000588020.1 First in ClinVar: Oct 22, 2016 Last updated: Oct 22, 2016
Benign (Dec 19, 2016)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000778729.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017
Benign (Mar 02, 2018)	no assertion criteria provided Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	True Health Diagnostics Accession: SCV000787916.1 First in ClinVar: Mar 24, 2017 Last updated: Mar 24, 2017
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: SCV000592321.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021	Comment: The p.Ile3412Val variant has been previously reported in the literature in 59 of 4707 (frequency of 0.006) probands with breast or esophageal cancer and was … (more) The p.Ile3412Val variant has been previously reported in the literature in 59 of 4707 (frequency of 0.006) probands with breast or esophageal cancer and was also identified in 33 of 5486 (frequency of 0.003) controls increasing the likelihood that this is a low frequency benign variant (Capanu_2011_21520273, Vehmanen_1997_ 9150152, Freedman_2004_15317758, Johnson_2007Â¬â‰ _17341484, Bergthorsson_2001_11389159, Kuusisto_2011_Â¬â‰ 21356067, Palmieri_2002_12453858, Hu_2004_14647438). The variant was also identified in the LOVD (4X), UMD (30X), and BIC (111X) databases. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs1801426) with a global minor allele frequency (MAF) of 0.043 (1000 genomes), increasing the likelihood that this is a low frequency benign variant. The Ile3412 residue is not highly conserved in mammals and computational analyses (SIFT, AlignGVGD) do not predict any effect on the protein function. In the UMD database, this variant has been identified in three individuals with a second pathogenic variant with a breast or ovarian cancer phenotype, and also found co-occurring with a deleterious BRCA2 mutation 1493delA in a cell line derived from a primary breast cancer (Teng 1996), thereby increasing the likelihood that this variant does not have clinical significance. In addition, Myriad genetics has reported this variant as a polymorphism increasing the likelihood this variant is benign (personal communication). In summary, based on the above information, this variant is classified as benign (less)
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001905736.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001956884.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely benign (-)	no assertion criteria provided Method: literature only	Familial cancer of breast Affected status: yes Allele origin: germline	Center for Precision Medicine, Meizhou People's Hospital Accession: SCV002520853.1 First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022	Publications: PubMed (5) PubMed: 22703879‚ 21356067‚ 17341484‚ 24884479‚ 23469205
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000084525.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic
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Comment:

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

The p.Ile3412Val variant has been previously reported in the literature in 59 of 4707 (frequency of 0.006) probands with breast or esophageal cancer and was also identified in 33 of 5486 (frequency of 0.003) controls increasing the likelihood that this is a low frequency benign variant (Capanu_2011_21520273, Vehmanen_1997_ 9150152, Freedman_2004_15317758, Johnson_2007Â¬â‰ _17341484, Bergthorsson_2001_11389159, Kuusisto_2011_Â¬â‰ 21356067, Palmieri_2002_12453858, Hu_2004_14647438). The variant was also identified in the LOVD (4X), UMD (30X), and BIC (111X) databases. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs1801426) with a global minor allele frequency (MAF) of 0.043 (1000 genomes), increasing the likelihood that this is a low frequency benign variant. The Ile3412 residue is not highly conserved in mammals and computational analyses (SIFT, AlignGVGD) do not predict any effect on the protein function. In the UMD database, this variant has been identified in three individuals with a second pathogenic variant with a breast or ovarian cancer phenotype, and also found co-occurring with a deleterious BRCA2 mutation 1493delA in a cell line derived from a primary breast cancer (Teng 1996), thereby increasing the likelihood that this variant does not have clinical significance. In addition, Myriad genetics has reported this variant as a polymorphism increasing the likelihood this variant is benign (personal communication). In summary, based on the above information, this variant is classified as 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Familial history and prevalence of BRCA1, BRCA2 and TP53 pathogenic variants in HBOC Brazilian patients from a public healthcare service.	Matta BP	Scientific reports	2022	PMID: 36329109
Prevalence of Clinically Relevant Germline BRCA Variants in a Large Unselected South African Breast and Ovarian Cancer Cohort: A Public Sector Experience.	Van der Merwe NC	Frontiers in genetics	2022	DOI: 10.3389/fgene.2022.834265
Hereditary breast and ovarian cancer: assessment of point mutations and copy number variations in Brazilian patients.	Silva FC	BMC medical genetics	2014	PMID: 24884479
Comprehensive analysis of BRCA1, BRCA2 and TP53 germline mutation and tumor characterization: a portrait of early-onset breast cancer in Brazil.	Carraro DM	PloS one	2013	PMID: 23469205
Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.	Johnston JJ	American journal of human genetics	2012	PMID: 22703879
Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals.	Kuusisto KM	Breast cancer research : BCR	2011	PMID: 21356067
Counting potentially functional variants in BRCA1, BRCA2 and ATM predicts breast cancer susceptibility.	Johnson N	Human molecular genetics	2007	PMID: 17341484
Common variation in BRCA2 and breast cancer risk: a haplotype-based analysis in the Multiethnic Cohort.	Freedman ML	Human molecular genetics	2004	PMID: 15317758
BRCA1 and BRCA2 mutation status and cancer family history of Danish women affected with multifocal or bilateral breast cancer at a young age.	Bergthorsson JT	Journal of medical genetics	2001	PMID: 11389159
A low proportion of BRCA2 mutations in Finnish breast cancer families.	Vehmanen P	American journal of human genetics	1997	PMID: 9150152
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRCA2	-	-	-	-
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Text-mined citations for rs1801426 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000059.4(BRCA2):c.10234A>G (p.Ile3412Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1801426 ...