NM_007294.3(BRCA1):c.3756_3759delGTCT (p.Ser1253Argfs) AND Hereditary breast and ovarian cancer syndrome

Clinical significance:Pathogenic (Last evaluated: Jan 7, 2018)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000167859.9

Allele description

NM_007294.3(BRCA1):c.3756_3759delGTCT (p.Ser1253Argfs)

Gene:
BRCA1:BRCA1, DNA repair associated [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
17q21.31
Genomic location:
Preferred name:
NM_007294.3(BRCA1):c.3756_3759delGTCT (p.Ser1253Argfs)
Other names:
3874del4; 3875_3878delGTCT
HGVS:
  • NC_000017.11:g.43091772_43091775delAGAC
  • NG_005905.2:g.126209_126212delGTCT
  • NM_007294.3:c.3756_3759delGTCT
  • NM_007298.3:c.788-743_788-740delGTCT
  • NP_009225.1:p.Ser1253Argfs
  • LRG_292t1:c.3756_3759delGTCT
  • LRG_292:g.126209_126212delGTCT
  • LRG_292p1:p.Ser1253Argfs
  • NC_000017.10:g.41243789_41243792delAGAC
  • NM_007294.3:c.3756_3759del
  • NR_027676.1:n.3892_3895delGTCT
  • U14680.1:c.3756_3759delGTCT
  • U14680.1:n.3875_3878delGTCT
  • p.S1253Rfs*10
  • p.S1253RfsX10
  • p.Ser1253Argfs*10
Nucleotide change:
3875del4
Links:
Breast Cancer Information Core (BIC) (BRCA1): 3874&base_change=del TGTC; Breast Cancer Information Core (BIC) (BRCA1): 3875&base_change=del GTCT; OMIM: 113705.0014; dbSNP: rs80357868
NCBI 1000 Genomes Browser:
rs80357868
Allele Frequency:
0.00003(-)
Molecular consequence:
  • NM_007294.3:c.3756_3759delGTCT - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_007298.3:c.788-743_788-740delGTCT - intron variant - [Sequence Ontology: SO:0001627]
  • NR_027676.1:n.3892_3895delGTCT - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Hereditary breast and ovarian cancer syndrome (HBOC)
Synonyms:
Hereditary breast and ovarian cancer
Identifiers:
MeSH: D061325; MedGen: C0677776; Orphanet: 145; OMIM: PS604370

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000076327Invitaecriteria provided, single submitter
Pathogenic
(Jan 7, 2018)
germlineclinical testing

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

SCV000587342Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR)no assertion criteria providedPathogenic
(Jan 31, 2014)
germlineresearch

SCV000591471Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)criteria provided, single submitter
Pathogenicgermlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV000699069Integrated Genetics/Laboratory Corporation of Americacriteria provided, single submitter
Pathogenic
(Apr 22, 2016)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Summary from all submissions

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

Citations

PubMed

Nonequivalent gene expression and copy number alterations in high-grade serous ovarian cancers with BRCA1 and BRCA2 mutations.

George J, Alsop K, Etemadmoghadam D, Hondow H, Mikeska T, Dobrovic A, deFazio A; Australian Ovarian Cancer Study Group., Smyth GK, Levine DA, Mitchell G, Bowtell DD.

Clin Cancer Res. 2013 Jul 1;19(13):3474-84. doi: 10.1158/1078-0432.CCR-13-0066. Epub 2013 Apr 30.

PubMed [citation]
PMID:
23633455

Contribution of germline mutations in the BRCA and PALB2 genes to pancreatic cancer in Italy.

Ghiorzo P, Pensotti V, Fornarini G, Sciallero S, Battistuzzi L, Belli F, Bonelli L, Borgonovo G, Bruno W, Gozza A, Gargiulo S, Mastracci L, Nasti S, Palmieri G, Papadia F, Pastorino L, Russo A, Savarino V, Varesco L, Bernard L, Bianchi ScarrĂ  G; Genoa Pancreatic Cancer Study Group..

Fam Cancer. 2012 Mar;11(1):41-7. doi: 10.1007/s10689-011-9483-5.

PubMed [citation]
PMID:
21989927
See all PubMed Citations (16)

Details of each submission

From Invitae, SCV000076327.9

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

Description

This sequence change creates a premature translational stop signal (p.Ser1253Argfs*10) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80357868, ExAC 0.004%). This variant has been reported in individuals affected with breast and/or ovarian cancer, and pancreatic cancer (PMID: 7894491, 21324516, 23633455, 21989927). This variant is also known as 3875del4 in the literature. ClinVar contains an entry for this variant (Variation ID: 17673). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.

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

From Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR), SCV000587342.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearchnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000591471.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Integrated Genetics/Laboratory Corporation of America, SCV000699069.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

Variant summary: The BRCA1 c.3756_3759delGTCT variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln1756fs). Mutation Taster predicts a damaging outcome for this variant. This variant was found in 3/121438 control chromosomes at a frequency of 0.0000247, which does not exceed maximal expected frequency of a pathogenic BRCA1 allele (0.0010005). The variant has been cited in multiple HBOC patients in the literature. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.

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

Last Updated: Sep 30, 2018

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