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NM_007294.4(BRCA1):c.661G>T (p.Ala221Ser)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(3);Uncertain significance(2)

Review status:
criteria provided, conflicting interpretations
Submissions:
7 (Most recent: Feb 26, 2020)
Last evaluated:
Nov 8, 2018
Accession:
VCV000037690.2
Variation ID:
37690
Description:
single nucleotide variant
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NM_007294.4(BRCA1):c.661G>T (p.Ala221Ser)

Allele ID
46246
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
17q21.31
Genomic location
17: 43095855 (GRCh38) GRCh38 UCSC
17: 41247872 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000017.10:g.41247872C>A
NC_000017.11:g.43095855C>A
NM_007294.4:c.661G>T MANE Select NP_009225.1:p.Ala221Ser missense
... more HGVS
Protein change
A221S
Other names
p.A221S:GCA>TCA
780G>T
Canonical SPDI
NC_000017.11:43095854:C:A
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Links
ClinGen: CA003780
dbSNP: rs80357088
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely benign 2 criteria provided, multiple submitters, no conflicts Nov 8, 2018 RCV000165438.4
Uncertain significance 3 criteria provided, single submitter Aug 11, 2016 RCV000031271.6
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Aug 29, 2017 RCV000200971.3
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
BRCA1 Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
11360 11515

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Aug 11, 2016)
criteria provided, single submitter
Method: clinical testing
Breast-ovarian cancer, familial 1
Allele origin: unknown
Counsyl
Accession: SCV000489036.1
Submitted: (Nov 23, 2016)
Evidence details
Publications
PubMed (3)
Uncertain significance
(Jul 20, 2017)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000600432.1
Submitted: (Aug 01, 2017)
Evidence details
Publications
PubMed (3)
Likely benign
(Apr 08, 2015)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color
Accession: SCV000683341.1
Submitted: (Oct 26, 2017)
Evidence details
Likely benign
(Aug 29, 2017)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
GeneDx
Accession: SCV000210081.11
Submitted: (Mar 26, 2018)
Evidence details
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)
Likely benign
(Nov 08, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000216167.3
Submitted: (Feb 26, 2020)
Evidence details
Comment:
Other data supporting benign classification;In silico models in agreement (benign)
Likely benign
(Jan 08, 2013)
no assertion criteria provided
Method: clinical testing
Breast-ovarian cancer, familial 1
Allele origin: germline
Sharing Clinical Reports Project (SCRP)
Accession: SCV000053876.4
Submitted: (Aug 20, 2015)
Evidence details
Uncertain significance
(May 29, 2002)
no assertion criteria provided
Method: clinical testing
Breast-ovarian cancer, familial 1
Allele origin: germline
Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000145647.1
Submitted: (Mar 28, 2014)
Evidence details

Functional evidence

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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.

Citations for this variant

Title Author Journal Year Link
Prediction of single-nucleotide substitutions that result in exon skipping: identification of a splicing silencer in BRCA1 exon 6. Raponi M Human mutation 2011 PMID: 21309043
Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations. Judkins T Cancer research 2005 PMID: 16267036
Evolution of the tumor suppressor BRCA1 locus in primates: implications for cancer predisposition. Pavlicek A Human molecular genetics 2004 PMID: 15385441
Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. Abkevich V Journal of medical genetics 2004 PMID: 15235020

Record last updated Nov 26, 2020