NM_000059.4:c.7007G>C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000059.4(BRCA2):c.7007G>C(p.Arg2336Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,450,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2336H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 4.66

Variant links:

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-32346896-G-A is described in Lovd as [Likely_pathogenic].

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 13-32346896-G-C is Pathogenic according to our data. Variant chr13-32346896-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 52241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32346896-G-C is described in Lovd as [Pathogenic]. Variant chr13-32346896-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.7007G>C	p.Arg2336Pro	missense_variant, splice_region_variant	Exon 13 of 27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.7007G>C	p.Arg2336Pro	missense_variant, splice_region_variant	Exon 13 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.6638G>C	p.Arg2213Pro	missense_variant, splice_region_variant	Exon 13 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.7007G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 12 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247222

Hom.:

AF XY:

0.00000748

AC XY:

AN XY:

133680

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1450870

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721902

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000385

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000804

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary breast ovarian cancer syndrome

Pathogenic:4

Oct 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 altered 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 produces a non-functional protein and/or introduces a premature termination codon (PMID: 22505045). 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. -

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Aug 23, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:3

May 05, 2006

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 04, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Sep 20, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.7007G>C (p.Arg2336Pro) variant has been reported in the published literature to cause skipping of exons 12 and 13 in the BRCA2 gene, resulting in a truncated protein (PMIDs: 9150172 (1997), 22505045 (2012)). This variant has been reported in multiple individuals and/or families affected with hereditary breast and/or ovarian cancer (PMIDs: 9150172 (1997), 20960228 (2011), 21063910 (2011), 22399190 (2012), 25256924 (2014), 28008555 (2017), 29560538 (2018), 31159747 (2019), 32438681 (2020)). It has also been reported in a compound heterozygous state with other pathogenic BRCA2 variants in individuals affected with Fanconi Amenia (PMIDs: 21548014 (2012), 28973083 (2017), 33461977 (2022)). The frequency of this variant in the general population, 0.000004 (1/247222 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, this variant is classified as pathogenic. -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: PM1, PM2, PM5, PS3:Moderate, PS4:Moderate -

Jan 30, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 7235G>C; This variant is associated with the following publications: (PMID: 29560538, 9150172, 22762150, 26913838, 21523855, 20960228, 26187060, 25256924, 22399190, 21063910, 24312913, 21548014, 28008555, 29086229, 30014164, 21465317, 28973083, 32444794, 30787465, 32341426, 32438681, 34687993, 22505045, 31131967) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Mar 06, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 31, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Breast-ovarian cancer, familial, susceptibility to, 1

Pathogenic:1

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:1

Sep 01, 2019

King Laboratory, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Fanconi anemia complementation group D1

Pathogenic:1

Nov 11, 2020

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast

Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Arg2336Pro variant has been previously reported in the literature in at least one individual with hereditary breast cancer (Laitman 2011). In addition, this variant has been previously reported in the UMD database (2x as causal), and the BIC database (5x as clinically relevant). The variant is also reported in dbSNP (rs28897743) and may be a low frequency pathogenic variant in one or more populations. The p.Arg2336Pro variant occurs in the last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, in one study, RNA was extracted from lymphoblastoid cell lines and an increase of alternative splicing was observed ('Exons 12 and 13 skipped'), increasing the likelihood this variant has clinical significance (Houdayer 2012). Another variant at the same position (c.7007G>A; p.Arg2336His) has been shown to induce aberrant splicing (Thomassen 2006), also increasing the likelihood a variant at this position is clinically significant. Furthermore, in-silico analysis (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing in 3 of 5 different programs. In summary, based on the above information, this variant is classified as Pathogenic. -

Familial cancer of breast

Pathogenic:1

Mar 05, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Benign

0.95

Eigen

Benign

-0.058

Eigen_PC

Benign

0.064

FATHMM_MKL

Uncertain

0.90

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.28

T;T

MetaSVM

Benign

-0.71

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.40

N;N

REVEL

Uncertain

0.42

Sift

Benign

0.24

T;T

Sift4G

Benign

0.26

T;T

Vest4

0.38

MutPred

0.43

Gain of glycosylation at R2336 (P = 0.0157);Gain of glycosylation at R2336 (P = 0.0157);

MVP

0.91

MPC

0.061

ClinPred

0.83

GERP RS

5.0

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.98

SpliceAI score (max)

0.18

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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