NM_000059.4(BRCA2):c.4211del (p.Thr1403_Ser1404insTer) AND Hereditary breast ovarian cancer syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 22, 2024
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:: RCV000462802.22

Allele description [Variation Report for NM_000059.4(BRCA2):c.4211del (p.Thr1403_Ser1404insTer)]

NM_000059.4(BRCA2):c.4211del (p.Thr1403_Ser1404insTer)

Gene:

BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.4211del (p.Thr1403_Ser1404insTer)

HGVS:

NC_000013.11:g.32338566del
NG_012772.3:g.28087del
NM_000059.4:c.4211delMANE SELECT
NP_000050.3:p.Thr1403_Ser1404insTer
LRG_293:g.28087del
NC_000013.10:g.32912703del
NC_000013.10:g.32912703delC
NM_000059.3:c.4211delC
NM_000059.4:c.4211del

Nucleotide change:

4439delC

Links:

dbSNP: rs398122777

NCBI 1000 Genomes Browser:

rs398122777

Molecular consequence:

NM_000059.4:c.4211del - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Hereditary breast ovarian cancer syndrome
Synonyms:: Hereditary breast and ovarian cancer syndrome; Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000549886	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 22, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20104584, 28492532
SCV000587703	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR)	no assertion criteria provided	Pathogenic (Jan 31, 2014)	germline	research
SCV001338002	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 6, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001653094	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Mar 14, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 29446198, 25151137, 30039884, 24033266

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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	research
not provided	germline	unknown	1	1	not provided	not provided	not provided	clinical 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

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

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000549886.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Ser1404*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 91815). 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), SCV000587703.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001338002.1

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

Description

Variant summary: BRCA2 c.4211delC (p.Ser1404X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 235862 control chromosomes. c.4211delC has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Rebbeck_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV001653094.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

The p.Ser1404X variant in BRCA2 has been reported in at least 2 individuals with BRCA2-associated cancers (Guan 2015 PMID: 25151137; Dong 2018 PMID: 30039884), in 1 individual with a family history of breast and ovarian cancer (HBOC) that had undergone clinical genetic testing (Rebbeck 2018 PMID: 29446198) and was absent from large population studies. This variant is a single base deletion that creates a premature termination codon at position 1404, resulting in a nonsense variant which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer (HBOC). Moreover, this variant was classified as pathogenic on September 13, 2016 by the ClinGen-approved ENIGMA expert panel and several clinical labs (Variation ID 91815). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PS4_Supporting.

#	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		1	not provided	1	not provided

Last Updated: Nov 10, 2024

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