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

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 24, 2022
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:: RCV000509746.16

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]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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gi|1883684667|ref|NM_054105.2|

Nucleotide
PMC Links for GEO Profiles (Select 72016415) (6)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000608244	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Aug 24, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25151137, 29446198 Citation Link,
SCV000683604	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 21, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25151137, 29446198, 30039884, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000608244

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Aug 24, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000683604

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 21, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Detection of inherited mutations for hereditary cancer using target enrichment and next generation sequencing.

Guan Y, Hu H, Peng Y, Gong Y, Yi Y, Shao L, Liu T, Li G, Wang R, Dai P, Bignon YJ, Xiao Z, Yang L, Mu F, Xiao L, Xie Z, Yan W, Xu N, Zhou D, Yi X.

Fam Cancer. 2015 Mar;14(1):9-18. doi: 10.1007/s10689-014-9749-9.

PubMed [citation]

PMID:: 25151137

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

Rebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A, Olah E, Olopade OI, Solano AR, Teo SH, Thomassen M, Weitzel JN, Chan TL, Couch FJ, Goldgar DE, Kruse TA, Palmero EI, Park SK, Torres D, van Rensburg EJ, McGuffog L, Parsons MT, et al.

Hum Mutat. 2018 May;39(5):593-620. doi: 10.1002/humu.23406. Epub 2018 Mar 12.

PubMed [citation]

PMID:: 29446198
PMCID:: PMC5903938

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000608244.5

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

Description

The c.4211delC pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 4211, causing a translational frameshift with a predicted alternate stop codon (p.S1404*). A different alteration (c.4211C>G) resulting in a stop codon at the same amino acid position (p.S1404*) was previously reported in a 48 year old man with prostate cancer (Guan Y et al. Fam. Cancer. 2015 Mar;14:9-18). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000683604.3

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

Description

This variant deletes 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in at least three suspected hereditary breast and ovarian cancer families (PMID: 29446198, 30039884) and a different mutation resulting in a stop codon at the same position has been reported in an individual affected with pancreatic cancer (PMID: 25151137). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, 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: Nov 10, 2024

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