NM_000059.4:c.7007G>C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM5PP5_Very_Strong

The NM_000059.4(BRCA2):ā€‹c.7007G>Cā€‹(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 (ā˜…ā˜…). 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 š‘“: 0.0000014 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense, splice_region

Scores

2
3
11
Splicing: ADA: 1.000
2

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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].
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
BRCA2NM_000059.4 linkc.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 Appris UniProt
BRCA2ENST00000380152.8 linkc.7007G>C p.Arg2336Pro missense_variant, splice_region_variant Exon 13 of 27 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.6638G>C p.Arg2213Pro missense_variant, splice_region_variant Exon 13 of 27 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.7007G>C splice_region_variant, non_coding_transcript_exon_variant Exon 12 of 26 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000404
AC:
1
AN:
247222
Hom.:
0
AF XY:
0.00000748
AC XY:
1
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:
2
AN:
1450870
Hom.:
0
Cov.:
29
AF XY:
0.00000277
AC XY:
2
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.:
32
Alfa
AF:
0.00000804
Hom.:
0

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
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. -

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). -

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. -

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) -

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 -

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
D
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
29
DANN
Benign
0.95
Eigen
Benign
-0.058
Eigen_PC
Benign
0.064
FATHMM_MKL
Uncertain
0.90
D
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.28
T;T
MetaSVM
Benign
-0.71
T
PrimateAI
Benign
0.22
T
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
D
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.

Other links and lift over

dbSNP: rs28897743; hg19: chr13-32921033; COSMIC: COSV66457358; API