NM_000059.3(BRCA2):c.4271C>G (p.Ser1424Cys) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(2) (Last evaluated: Jan 7, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000590783.1

Allele description [Variation Report for NM_000059.3(BRCA2):c.4271C>G (p.Ser1424Cys)]

NM_000059.3(BRCA2):c.4271C>G (p.Ser1424Cys)

Gene:
BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
13q13.1
Genomic location:
Preferred name:
NM_000059.3(BRCA2):c.4271C>G (p.Ser1424Cys)
HGVS:
  • NC_000013.11:g.32338626C>G
  • NG_012772.3:g.28147C>G
  • NM_000059.3:c.4271C>G
  • NP_000050.2:p.Ser1424Cys
  • LRG_293t1:c.4271C>G
  • LRG_293:g.28147C>G
  • LRG_293p1:p.Ser1424Cys
  • NC_000013.10:g.32912763C>G
  • NM_000059.4:c.4271C>GMANE SELECT
  • U43746.1:n.4499C>G
  • p.S1424C
Protein change:
S1424C
Links:
dbSNP: rs80358664
NCBI 1000 Genomes Browser:
rs80358664
Molecular consequence:
  • NM_000059.3:c.4271C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000329136GeneDxcriteria provided, single submitter
Uncertain significance
(Jan 7, 2019)
germlineclinical testing

Citation Link,

SCV000694761Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Mar 17, 2017)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000885083ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Likely benign
(Jul 23, 2017)
germlineclinical testing

Citation Link

Summary from all submissions

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

Citations

PubMed

Pathogenicity evaluation of BRCA1 and BRCA2 unclassified variants identified in Portuguese breast/ovarian cancer families.

Santos C, Peixoto A, Rocha P, Pinto P, Bizarro S, Pinheiro M, Pinto C, Henrique R, Teixeira MR.

J Mol Diagn. 2014 May;16(3):324-34. doi: 10.1016/j.jmoldx.2014.01.005. Epub 2014 Mar 5.

PubMed [citation]
PMID:
24607278

Impact of BRCA1 and BRCA2 variants on splicing: clues from an allelic imbalance study.

Caux-Moncoutier V, Pagès-Berhouet S, Michaux D, Asselain B, Castéra L, De Pauw A, Buecher B, Gauthier-Villars M, Stoppa-Lyonnet D, Houdayer C.

Eur J Hum Genet. 2009 Nov;17(11):1471-80. doi: 10.1038/ejhg.2009.89. Epub 2009 May 27.

PubMed [citation]
PMID:
19471317
PMCID:
PMC2986693
See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000329136.6

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

Description

This variant is denoted BRCA2 c.4271C>G at the cDNA level, p.Ser1424Cys (S1424C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). Using alternate nomenclature, this variant would be defined as BRCA2 4499C>G. This variant was observed in at least three individuals with breast cancer and one individual with lung cancer (Spearman 2008, Haffty 2009, Lu, 2015, Wong-Brown 2015). This variant was predicted to be neutral by a model based on aspects of tumor pathology and genetics including receptor status, tumor grade, loss of heterozygosity, and presence of deleterious variants in trans (Spearman 2008). In addition, this variant was identified in a individual with breast cancer and a family history of breast and ovarian cancer (Santos 2014). However, this family was also identified to carry a pathogenic BRCA1 variant and BRCA2 Ser1424Cys was not identified in the individual with an early-onset ovarian cancer (Santos 2014). BRCA2 Ser1424Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the BRC3 domain and the POLH binding domain (Cole 2011, Buisson 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ser1424Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694761.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: The BRCA2 c.4271C>G (p.Ser1424Cys) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution. The variant lies within the BRC3 domain (UMD) and the POLH binding domain (UniProt). 3/5 in silico tools predict a benign outcome for this variant. This variant is absent in the large control database ExAC (0/119534 control chromosomes). Several publications have cited the variant and categorized it as neutral (Spearman_JCO_2008; Santos_BRCA1&2_JMD_2014) or variant of unknown significance (Caux-Moncoutier_HM_2011; Hafty_BRCA1&2_Annals of Oncology_2009; Wong-Brown_BRCA1&2_BCRT_2015). Additionally, Santos_BRCA1&2_JMD_2014 found that the variant did not co-segregate completely in family study (4 of 5 affected family members had the variant) and identified a co-occurring BRCA1 pathogenic mutation in the same family, although precise information on the mutation and which family members were carriers was not provided. Another BRCA1 pathogenic co-occurrence with the variant was also found in the BIC database, although overlap with the Santos study cannot be unequivocally ruled out. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. Taken together, this variant is classified as VUS-possibly benign until more evidence becomes available.

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

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV000885083.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 18, 2021

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