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

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Oct 10, 2023
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:: RCV000045113.24

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 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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Saccharomyces cerevisiae S288C Rgl1p (RGL1), partial mRNA
Saccharomyces cerevisiae S288C Rgl1p (RGL1), partial mRNA
gi|296148588|ref|NM_001183880.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000073126	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 10, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 9150172, 20960228, 21548014, 22399190, 17576681, 9536098, 16792514, 20215541, 22505045, 28492532
SCV000587879	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
SCV000695023	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 23, 2017)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 28008555, 20960228, 25256924, 21465317, 22505045, 9150172, 22399190 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000821714	GeneKor MSA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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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
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, research

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

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

See all PubMed Citations (14)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000073126.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 2336 of the BRCA2 protein (p.Arg2336Pro). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs28897743, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer and Fanconi anemia (PMID: 9150172, 20960228, 21548014, 22399190). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 7235G>C. ClinVar contains an entry for this variant (Variation ID: 52241). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exons 12 and 13 and introduces a premature termination codon (PMID: 22505045). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the c.7007G nucleotide in the BRCA2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 16792514, 20215541, 22505045). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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), SCV000587879.1

#	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, SCV000695023.1

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

Description

Variant summary: The BRCA2 c.7007G>C (p.Arg2336Pro) variant involves the alteration of a conserved nucleotide affecting the last nucleotide of the exon 13. 3/5 in silico tools predict damaging outcome for this variant. 4/5 splice prediction tools predict a significant impact on normal splicing. ESE finder predicts that this variant may generate a novel ESE site. Functional studies showed that the variant causes skipping of exons 12 and 13 (and increase of alternative splicing) (Serova-Sinilnikova, 1997, Houdayer, 2012). This variant is absent in 115936 control chromosomes from ExAC. The variant was found in multiple individuals with a personal/or family history of breast and/or ovarian cancer (Serova-Sinilnikova 1997, Sagi 2010, Adams 2011, Laitman 2011, Laitman 2012, Pritzlaff 2017, Wang 2014). In addition, several clinical diagnostic laboratories/reputable databases have 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

From GeneKor MSA, SCV000821714.2

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

Description

This variation replaces Arginine with Proline at codon 2336 of the BRCA2 protein. The arginine residue is weakly conserved and is located in a domain of the protein that is not known to be functionally important. There is a moderate physicochemical difference between arginine and proline (Grantham Score 81). This variant also falls at the last nucleotide of exon 13 of the BRCA2 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (rs28897743, ExAC no frequency). This variant has been reported in individuals with breast and/or ovarian cancer and Fanconi anemia (PMID: 9150172, PMID: 22399190, PMID: 21548014 ). This variant is also known as 7235G>C in the literature. Experimental studies have shown that this missense change causes skipping of exons 12 and 13 (PMID: 22505045). The mutation database ClinVar contains entries for this variant (Variation ID: 52241).

#	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

Last Updated: Nov 3, 2024

ClinVar

Relating variation to medicine