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NM_007294.4(BRCA1):c.5165C>A (p.Ser1722Tyr)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(1);Uncertain significance(2)

Review status:
criteria provided, conflicting interpretations
Submissions:
4 (Most recent: Jan 7, 2021)
Last evaluated:
Mar 5, 2020
Accession:
VCV000491098.9
Variation ID:
491098
Description:
single nucleotide variant
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NM_007294.4(BRCA1):c.5165C>A (p.Ser1722Tyr)

Allele ID
484900
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
17q21.31
Genomic location
17: 43063361 (GRCh38) GRCh38 UCSC
17: 41215378 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_292:g.154623C>A
LRG_292t1:c.5165C>A LRG_292p1:p.Ser1722Tyr
NC_000017.10:g.41215378G>T
... more HGVS
Protein change
S1722Y, S1675Y, S1743Y, S618Y
Other names
-
Canonical SPDI
NC_000017.11:43063360:G:T
Functional consequence
function_uncertain_variant [Sequence Ontology SO:0002220]
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5165C>A, a MISSENSE variant, produced a function score of -1.28, corresponding to a functional classification of INTERMEDIATE. SGE function score ranges for classification are as follows: ‘functional’, score > -0.748; ‘intermediate’, -0.748 > score > -1.328; ‘non-functional’, score < -1.328. The median synonymous SNV scored 0.0 and the median nonsense SNV scored -2.12. [submitted by Brotman Baty Institute,University of Washington]
Global minor allele frequency (GMAF)
-

Allele frequency
-
Links
ClinGen: CA10591215
dbSNP: rs80357104
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 1 criteria provided, single submitter Nov 21, 2019 RCV000637560.3
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Mar 5, 2020 RCV000582258.5
not provided 1 no assertion provided - RCV001077730.1
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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
12040 12208

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Jun 22, 2019)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV000688544.3
Submitted: (May 19, 2020)
Evidence details
Likely pathogenic
(Mar 05, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV001185556.2
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (3)
Comment:
The p.S1722Y variant (also known as c.5165C>A), located in coding exon 17 of the BRCA1 gene, results from a C to A substitution at nucleotide … (more)
Uncertain significance
(Nov 21, 2019)
criteria provided, single submitter
Method: clinical testing
Hereditary breast and ovarian cancer syndrome
Allele origin: germline
Invitae
Accession: SCV000759024.4
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (4)
Comment:
This sequence change replaces serine with tyrosine at codon 1722 of the BRCA1 protein (p.Ser1722Tyr). The serine residue is highly conserved and there is a … (more)
not provided
(-)
no assertion provided
Method: in vitro
Breast-ovarian cancer, familial 1
Allele origin: not applicable
Brotman Baty Institute,University of Washington
Accession: SCV001243707.1
Submitted: (Nov 12, 2018)
Evidence details
Publications
PubMed (1)

Functional evidence

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Functional consequence Method Result Submitter Supporting information
function_uncertain_variant
  1. saturation genome editing in haploid cells
  2. Method citation(s):
  1. INTERMEDIATE:-1.284016223324
Brotman Baty Institute,University of Washington
Accession: SCV001243707.1
Submitted: (Nov 12, 2018)
Evidence details
Publications
PubMed (1)
Comment:
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5165C>A, a MISSENSE variant, produced a function score of -1.28, corresponding to a functional classification of INTERMEDIATE. … (more)

Citations for this variant

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Title Author Journal Year Link
Combining Homologous Recombination and Phosphopeptide-binding Data to Predict the Impact of <i>BRCA1</i> BRCT Variants on Cancer Risk. Petitalot A Molecular cancer research : MCR 2019 PMID: 30257991
Accurate classification of BRCA1 variants with saturation genome editing. Findlay GM Nature 2018 PMID: 30209399
Structure of BRCA1-BRCT/Abraxas Complex Reveals Phosphorylation-Dependent BRCT Dimerization at DNA Damage Sites. Wu Q Molecular cell 2016 PMID: 26778126
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. Pruss D Breast cancer research and treatment 2014 PMID: 25085752
Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. Lee MS Cancer research 2010 PMID: 20516115
Mutations in the BRCT domain confer temperature sensitivity to BRCA1 in transcription activation. Carvalho MA Cancer biology & therapy 2002 PMID: 12496477
https://sge.gs.washington.edu/BRCA1/ - - - -

Text-mined citations for rs80357104...

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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 Dec 04, 2021