VCV000381969.18 - ClinVar

NM_000059.4(BRCA2):c.6640A>G (p.Thr2214Ala)

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.

(5)

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(3); Likely benign(2)

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.6640A>G (p.Thr2214Ala)

Variation ID: 381969 Accession: VCV000381969.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q13.1 13: 32340995 (GRCh38) [ NCBI UCSC ] 13: 32915132 (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	Mar 8, 2017	May 1, 2024	Jan 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.6640A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Thr2214Ala	missense
NC_000013.11:g.32340995A>G
NC_000013.10:g.32915132A>G
NG_012772.3:g.30516A>G
LRG_293:g.30516A>G
LRG_293t1:c.6640A>G	LRG_293p1:p.Thr2214Ala

... more HGVS ... less HGVS

Protein change

T2214A

Other names

Canonical SPDI

NC_000013.11:32340994: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.

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

Links

ClinGen: CA16606429 dbSNP: rs377200598 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 breast ovarian cancer syndrome	Uncertain significance (1)	criteria provided, single submitter	May 23, 2023	RCV000689694.16
Hereditary cancer-predisposing syndrome	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Jan 8, 2024	RCV000775914.18
not provided	Likely benign (1)	criteria provided, single submitter	May 9, 2018	RCV001703679.9

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 09, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000521706.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017
Uncertain significance (May 23, 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: SCV000817358.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 28492532 Comment: ClinVar contains an entry for this variant (Variation ID: 381969). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. … (more) ClinVar contains an entry for this variant (Variation ID: 381969). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2214 of the BRCA2 protein (p.Thr2214Ala). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Jan 08, 2024)	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: SCV000910401.3 First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 31131967‚ 33471991 Comment: This missense variant replaces threonine with alanine at codon 2214 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces threonine with alanine at codon 2214 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control meta-analysis, this variant was reported in 1/60466 cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001245). This variant has also been reported in a multifactorial analysis with tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 1.07, 1.0246 and 0.767, respectively (PMID: 31131967). 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 (Mar 04, 2019)	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: SCV001187686.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Comment: The p.T2214A variant (also known as c.6640A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide … (more) The p.T2214A variant (also known as c.6640A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 6640. The threonine at codon 2214 is replaced by alanine, an amino acid with similar properties. This amino acid position is poorly 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 (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: SCV003847328.1 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).

Comment:

ClinVar contains an entry for this variant (Variation ID: 381969). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2214 of the BRCA2 protein (p.Thr2214Ala). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

This missense variant replaces threonine with alanine at codon 2214 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control meta-analysis, this variant was reported in 1/60466 cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001245). This variant has also been reported in a multifactorial analysis with tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 1.07, 1.0246 and 0.767, respectively (PMID: 31131967). 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.T2214A variant (also known as c.6640A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 6640. The threonine at codon 2214 is replaced by alanine, an amino acid with similar properties. This amino acid position is poorly 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.

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
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
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
Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.	Parsons MT	Human mutation	2019	PMID: 31131967

Text-mined citations for rs377200598 ...

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.6640A>G (p.Thr2214Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs377200598 ...