NM_007294.3(BRCA1):c.2338C>T (p.Gln780Ter) AND Hereditary breast and ovarian cancer syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Sep 4, 2017
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000047805.7

Allele description

NM_007294.3(BRCA1):c.2338C>T (p.Gln780Ter)

Gene:

BRCA1:BRCA1, DNA repair associated [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.31

Genomic location:

Preferred name:

NM_007294.3(BRCA1):c.2338C>T (p.Gln780Ter)

HGVS:

NC_000017.11:g.43093193G>A
NG_005905.2:g.124791C>T
NM_007294.3:c.2338C>T
NM_007298.3:c.787+1551C>T
NM_007300.3:c.2338C>T
NP_009225.1:p.Gln780Ter
NP_009231.2:p.Gln780Ter
LRG_292t1:c.2338C>T
LRG_292:g.124791C>T
LRG_292p1:p.Gln780Ter
NC_000017.10:g.41245210G>A
NR_027676.1:n.2474C>T
U14680.1:n.2457C>T
p.Gln780*
p.Gln780X
p.Q780*

Nucleotide change:

2457C>T

Protein change:

Q780*

Links:

dbSNP: rs80356945

Molecular consequence:

NM_007298.3:c.787+1551C>T - intron variant - [Sequence Ontology: SO:0001627]
NR_027676.1:n.2474C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_007294.3:c.2338C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000075818	Invitae	criteria provided, single submitter (Nykamp K et al. (Genet Med 2017))	Pathogenic (Sep 4, 2017)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 21324516, 22752604, 9667259, 7663517, 22006311, 16683254, 28492532
SCV000587206	Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR)	no assertion criteria provided	Pathogenic (Jan 22, 2015)	germline	research
SCV000588039	Department of Pathology and Molecular Medicine,Queen's University - The Canadian Open Genetics Repository (COGR)	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 20, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000591380	Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 9667259, 14760071, 16615107, 7663517, 22752604, 21324516, 25741868
SCV000605748	Laboratory for Molecular Medicine,Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine)	criteria provided, single submitter (LMM Criteria)	Pathogenic (Oct 28, 2016)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 9667259, 22752604, 7663517, 11802209, 22006311, 21324516, 16683254, 24033266
SCV000698940	Integrated Genetics/Laboratory Corporation of America	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 3, 2016)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16267036, 11802209, 8533757 LabCorp Variant Classification Summary - May 2015.docx Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

MYC is amplified in BRCA1-associated breast cancers.

Grushko TA, Dignam JJ, Das S, Blackwood AM, Perou CM, Ridderstråle KK, Anderson KN, Wei MJ, Adams AJ, Hagos FG, Sveen L, Lynch HT, Weber BL, Olopade OI.

Clin Cancer Res. 2004 Jan 15;10(2):499-507.

PubMed [citation]

PMID:: 14760071

See all PubMed Citations (14)

Details of each submission

From Invitae, SCV000075818.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change creates a premature translational stop signal (p.Gln780*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with breast and/or ovarian cancer (PMID: 7663517, 9667259, 16683254, 21324516, 22006311, 22752604). It is also known as 2457C>T, Q780X in the literature. ClinVar contains an entry for this variant (Variation ID: 54540). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR), SCV000587206.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pathology and Molecular Medicine,Queen's University - The Canadian Open Genetics Repository (COGR), SCV000588039.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000591380.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine,Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine), SCV000605748.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (8)

Description

The p.Gln780X variant in BRCA1 has been reported in >30 individuals with BRCA1-associated cancers (Hogervorst 1995, Frank 1998, Meindl 2002, van der Hout 2006, Walsh 2011, Zhang 2011, Juwle 2012, Breast Cancer Information Core (BIC) database). This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 780, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individuals with hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282277.1). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From Integrated Genetics/Laboratory Corporation of America, SCV000698940.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: The BRCA1 c.2338C>T (p.Gln780X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.2389G>T/p.Glu797X). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121352 control chromosomes. This variant has been reported in many HBOC patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 30, 2018

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