VCV000483126.26 - ClinVar

NM_000059.4(BRCA2):c.6554C>T (p.Ala2185Val)

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.

Conflicting classifications of pathogenicity
Uncertain significance(5); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000059.4(BRCA2):c.6554C>T (p.Ala2185Val)

Variation ID: 483126 Accession: VCV000483126.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q13.1 13: 32340909 (GRCh38) [ NCBI UCSC ] 13: 32915046 (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	Sep 16, 2024	Sep 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.6554C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Ala2185Val	missense
NC_000013.11:g.32340909C>T
NC_000013.10:g.32915046C>T
NG_012772.3:g.30430C>T
LRG_293:g.30430C>T
LRG_293t1:c.6554C>T	LRG_293p1:p.Ala2185Val

... more HGVS ... less HGVS

Protein change

A2185V

Other names

Canonical SPDI

NC_000013.11:32340908:C: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA247514034 dbSNP: rs980859921 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	18967	19126

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	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Apr 25, 2023	RCV000574498.14
Hereditary breast ovarian cancer syndrome	Likely benign (1)	criteria provided, single submitter	Oct 14, 2023	RCV000709328.14
Breast-ovarian cancer, familial, susceptibility to, 2	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 1, 2023	RCV000989053.4
BRCA2-related disorder	Uncertain significance (1)	criteria provided, single submitter	Jun 1, 2023	RCV004527661.1
Hereditary cancer	Likely benign (1)	criteria provided, single submitter	Sep 11, 2024	RCV004701665.1

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 (Jan 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807777.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PM2 moderated Number of individuals with the variant: 1 Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Likely benign (Mar 23, 2023)	criteria provided, single submitter (Dines et al. (Genet Med. 2020)) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	University of Washington Department of Laboratory Medicine, University of Washington Accession: SCV003847267.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 Comment: BRCA2 exon 11 coldspot. Reclassification based on statistical prior probability.	Publications: PubMed (1) PubMed: 31911673 Comment: Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Uncertain significance (Jun 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	BRCA2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004107173.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The BRCA2 c.6554C>T variant is predicted to result in the amino acid substitution p.Ala2185Val. This variant has been reported and classified as a variant of … (more) The BRCA2 c.6554C>T variant is predicted to result in the amino acid substitution p.Ala2185Val. This variant has been reported and classified as a variant of uncertain significance in patients with breast cancer (Fernandes et al. 2016. PubMed ID: 27741520; Bandeira et al. 2020. PubMed ID: 32986223). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Likely benign (Oct 14, 2023)	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: SCV000952384.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024
Uncertain significance (Jun 21, 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: SCV000688986.4 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 27741520‚ 32986223 Comment: This missense variant replaces alanine with valine at codon 2185 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces alanine with valine at codon 2185 of the BRCA2 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 individuals affected with breast cancer (PMID: 27741520, 32986223). This variant has not been identified 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 (Dec 01, 2023)	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: SCV004844280.1 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)	Publications: PubMed (2) PubMed: 27741520‚ 32986223 Comment: This missense variant replaces alanine with valine at codon 2185 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces alanine with valine at codon 2185 of the BRCA2 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 individuals affected with breast cancer (PMID: 27741520, 32986223). This variant has not been identified 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) Number of individuals with the variant: 1
Uncertain significance (Apr 25, 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: SCV000668841.6 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 27741520‚ 35264596 Comment: The p.A2185V variant (also known as c.6554C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide … (more) The p.A2185V variant (also known as c.6554C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 6554. The alanine at codon 2185 is replaced by valine, an amino acid with similar properties. This alteration has been reported in 1/349 Brazilian high-risk breast/ovarian cancer families, and the proband carrying this variant was diagnosed with breast cancer at age 31 and had two close relatives with breast cancer (Fernandes GC et al. Oncotarget, 2016 Dec;7:80465-80481). In addition, this alteration was detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Likely benign (Sep 11, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001139153.2 First in ClinVar: Jan 09, 2020 Last updated: Sep 16, 2024	Comment: This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in … (more) This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. (less)

Comment:

The BRCA2 c.6554C>T variant is predicted to result in the amino acid substitution p.Ala2185Val. This variant has been reported and classified as a variant of uncertain significance in patients with breast cancer (Fernandes et al. 2016. PubMed ID: 27741520; Bandeira et al. 2020. PubMed ID: 32986223). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Comment:

This missense variant replaces alanine with valine at codon 2185 of the BRCA2 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 individuals affected with breast cancer (PMID: 27741520, 32986223). This variant has not been identified 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:

The p.A2185V variant (also known as c.6554C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 6554. The alanine at codon 2185 is replaced by valine, an amino acid with similar properties. This alteration has been reported in 1/349 Brazilian high-risk breast/ovarian cancer families, and the proband carrying this variant was diagnosed with breast cancer at age 31 and had two close relatives with breast cancer (Fernandes GC et al. Oncotarget, 2016 Dec;7:80465-80481). In addition, this alteration was detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.

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
Detection of germline variants in Brazilian breast cancer patients using multigene panel testing.	Guindalini RSC	Scientific reports	2022	PMID: 35264596
Germline variants of Brazilian women with breast cancer and detection of a novel pathogenic ATM deletion in early-onset breast cancer.	Bandeira G	Breast cancer (Tokyo, Japan)	2021	PMID: 32986223
Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".	Dines JN	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 31911673
Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at-risk for hereditary breast cancer and characterization of its genetic ancestry.	Fernandes GC	Oncotarget	2016	PMID: 27741520

Text-mined citations for rs980859921 ...

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 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000059.4(BRCA2):c.6554C>T (p.Ala2185Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs980859921 ...