NM_000059.4(BRCA2):c.7007G>C (p.Arg2336Pro) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 31, 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:: RCV000214499.19

Allele description [Variation Report for NM_000059.4(BRCA2):c.7007G>C (p.Arg2336Pro)]

NM_000059.4(BRCA2):c.7007G>C (p.Arg2336Pro)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.7007G>C (p.Arg2336Pro)

HGVS:

NC_000013.11:g.32346896G>C
NG_012772.3:g.36417G>C
NM_000059.4:c.7007G>CMANE SELECT
NP_000050.2:p.Arg2336Pro
NP_000050.3:p.Arg2336Pro
LRG_293t1:c.7007G>C
LRG_293:g.36417G>C
LRG_293p1:p.Arg2336Pro
NC_000013.10:g.32921033G>C
NM_000059.3:c.7007G>C
U43746.1:n.7235G>C

Nucleotide change:

7235G>C

Protein change:

R2336P

Links:

dbSNP: rs28897743

NCBI 1000 Genomes Browser:

rs28897743

Molecular consequence:

NM_000059.4:c.7007G>C - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

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RecName: Full=Stannin
RecName: Full=Stannin
gi|48429132|sp|P61808.1|SNN_RAT

Protein
Saccharomyces cerevisiae S288C Vik1p (VIK1), partial mRNA
Saccharomyces cerevisiae S288C Vik1p (VIK1), partial mRNA
gi|296148407|ref|NM_001184067.1|

Nucleotide
Caenorhabditis elegans Ovule protein (F54C9.3), partial mRNA
Caenorhabditis elegans Ovule protein (F54C9.3), partial mRNA
gi|1831508720|ref|NM_063408.7|

Nucleotide
uncharacterized protein SPAPADRAFT_58853 [Spathaspora passalidarum NRRL Y-27907]
uncharacterized protein SPAPADRAFT_58853 [Spathaspora passalidarum NRRL Y-27907]
gi|598064459|ref|XP_007373058.1|

Protein
ahsa-1 Activator of Hsp90 ATPase AHSA1-like N-terminal domain-containing protein...
ahsa-1 Activator of Hsp90 ATPase AHSA1-like N-terminal domain-containing protein [Caenorhabditis elegans]
Gene ID:180017

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000276750	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 20960228, 21063910, 21548014, 22399190, 22505045, 28973083, 29560538, 30014164, 31159747, 32438681, 33293522, 9150172 Citation Link,
SCV000683838	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 6, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 9150172, 20960228, 21063910, 22399190, 22505045, 28008555, 32438681, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000276750

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 31, 2024)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

Citation Link,

SCV000683838

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 6, 2023)

germline

clinical testing

PubMed (8)
[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

The clinical phenotype of children with Fanconi anemia caused by biallelic FANCD1/BRCA2 mutations.

Myers K, Davies SM, Harris RE, Spunt SL, Smolarek T, Zimmerman S, McMasters R, Wagner L, Mueller R, Auerbach AD, Mehta PA.

Pediatr Blood Cancer. 2012 Mar;58(3):462-5. doi: 10.1002/pbc.23168. Epub 2011 May 5.

PubMed [citation]

PMID:: 21548014

Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management.

Meng L, Pammi M, Saronwala A, Magoulas P, Ghazi AR, Vetrini F, Zhang J, He W, Dharmadhikari AV, Qu C, Ward P, Braxton A, Narayanan S, Ge X, Tokita MJ, Santiago-Sim T, Dai H, Chiang T, Smith H, Azamian MS, Robak L, Bostwick BL, et al.

JAMA Pediatr. 2017 Dec 4;171(12):e173438. doi: 10.1001/jamapediatrics.2017.3438. Epub 2017 Dec 4.

PubMed [citation]

PMID:: 28973083
PMCID:: PMC6359927

See all PubMed Citations (14)

Details of each submission

From Ambry Genetics, SCV000276750.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

The c.7007G>C pathogenic mutation (also known as p.R2336P), located in coding exon 12 of the BRCA2 gene, results from a G to C substitution at nucleotide position 7007. The amino acid change results in arginine to proline at codon 2336, an amino acid with dissimilar properties. This change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Houdayer C et al. Hum. Mutat. 2012 Aug; 33(8):1228-38; Ambry internal data). In addition, this mutation has been reported in numerous individuals with breast and/or ovarian cancer (Serova-Sinilnikova OM et al. Am. J. Hum. Genet. 1997 May; 60(5):1236-9; Laitman Y et al. Breast Cancer Res. Treat. 2011 Jun; 127(2):489-95; Sagi M et al. Fam. Cancer 2011 Mar; 10(1):59-63; Santonocito C et al. Cancers (Basel), 2020 May;12; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Schayek H et al. Breast Cancer Res Treat, 2018 Jul;170:399-404) and has been described as a founder mutation in the Balkan Jewish population (Barnes-Kedar I et al. Breast Cancer Res Treat, 2018 Nov;172:151-157). This mutation has also been detected in conjunction with a nonsense mutation in BRCA2 in an individual with Fanconi anemia (Meng L et al. JAMA Pediatr. 2017 12;171(12):e173438). Of note, this alteration is also designated as 7235G>C in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.

#	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, SCV000683838.5

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

Description

This missense variant replaces arginine with proline at codon 2336 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant also changes the conserved G at the last nucleotide of exon 13 of the BRCA2 gene and is predicted to disrupt RNA splicing. An RNA study has shown that this variant causes skipping of exons 12 and 13, creating a premature translation stop signal in the RNA transcript (PMID: 22505045). This aberrant transcript is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 9150172, 20960228, 21063910, 22399190, 28008555, 32438681). This variant has been identified in 1/247222 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same nucleotide position, c.7007G>A (ClinVar variation ID: 38077), has been shown to produce aberrant RNA transcripts and is considered to be disease-causing. This finding indicates that the reference G nucleotide at the c.7007 position is important for normal RNA splicing. 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 3, 2024

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