NM_007294.4(BRCA1):c.1609A>G (p.Asn537Asp) AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Aug 27, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000605647.3

Allele description [Variation Report for NM_007294.4(BRCA1):c.1609A>G (p.Asn537Asp)]

NM_007294.4(BRCA1):c.1609A>G (p.Asn537Asp)

Gene:
BRCA1:BRCA1 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q21.31
Genomic location:
Preferred name:
NM_007294.4(BRCA1):c.1609A>G (p.Asn537Asp)
HGVS:
  • NC_000017.11:g.43093922T>C
  • NG_005905.2:g.124062A>G
  • NM_007294.3:c.1609A>G
  • NM_007294.4:c.1609A>GMANE SELECT
  • NM_007297.4:c.1468A>G
  • NM_007298.3:c.787+822A>G
  • NM_007299.4:c.787+822A>G
  • NM_007300.4:c.1609A>G
  • NP_009225.1:p.Asn537Asp
  • NP_009225.1:p.Asn537Asp
  • NP_009228.2:p.Asn490Asp
  • NP_009231.2:p.Asn537Asp
  • LRG_292t1:c.1609A>G
  • LRG_292:g.124062A>G
  • LRG_292p1:p.Asn537Asp
  • NC_000017.10:g.41245939T>C
  • NR_027676.2:n.1786A>G
  • p.N537D
Nucleotide change:
1728A>G
Protein change:
N490D
Links:
dbSNP: rs398122639
NCBI 1000 Genomes Browser:
rs398122639
Molecular consequence:
  • NM_007298.3:c.787+822A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007299.4:c.787+822A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007294.3:c.1609A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007294.4:c.1609A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007297.4:c.1468A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007300.4:c.1609A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_027676.2:n.1786A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000729886GeneDxcriteria provided, single submitter
Likely benign
(Nov 9, 2017)
germlineclinical testing

Citation Link,

SCV000918681Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Aug 27, 2019)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.

Borg A, Haile RW, Malone KE, Capanu M, Diep A, Törngren T, Teraoka S, Begg CB, Thomas DC, Concannon P, Mellemkjaer L, Bernstein L, Tellhed L, Xue S, Olson ER, Liang X, Dolle J, Børresen-Dale AL, Bernstein JL.

Hum Mutat. 2010 Mar;31(3):E1200-40. doi: 10.1002/humu.21202.

PubMed [citation]
PMID:
20104584
PMCID:
PMC2928257

Assessment of rare BRCA1 and BRCA2 variants of unknown significance using hierarchical modeling.

Capanu M, Concannon P, Haile RW, Bernstein L, Malone KE, Lynch CF, Liang X, Teraoka SN, Diep AT, Thomas DC, Bernstein JL; WECARE Study Collaborative Group., Begg CB.

Genet Epidemiol. 2011 Jul;35(5):389-97. doi: 10.1002/gepi.20587. Epub 2011 Apr 25.

PubMed [citation]
PMID:
21520273
PMCID:
PMC3111904
See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000729886.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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 a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918681.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: BRCA1 c.1609A>G (p.Asn537Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250852 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1609A>G has been reported in the literature in individuals affected with Breast Cancer. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and reported the variant with conflicting assessments (3 calling it Likely benign, while 2 classifying it as a VUS). Based on the evidence outlined above, the variant was classified as uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 14, 2021

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