chr13-32346896-G-T

Variant names:

• chr13-32346896-G-T
• rs28897743
• NM_000059.4:c.7007G>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.7007G>T​(p.Arg2336Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000689 in 1,450,868 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2336C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense, splice_region
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 4.66
• Publications: 113 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 13 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 ClinVar as Pathogenic. ClinVar VariationId is 38077.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 13-32346896-G-T is Pathogenic according to our data. Variant chr13-32346896-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 52242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.7007G>T	p.Arg2336Leu	missense splice_region	Exon 13 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.7007G>T	p.Arg2336Leu	missense splice_region	Exon 13 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.7007G>T	p.Arg2336Leu	missense splice_region	Exon 13 of 27	NP_001393649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.7007G>T	p.Arg2336Leu	missense splice_region	Exon 13 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.7007G>T	p.Arg2336Leu	missense splice_region	Exon 13 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.6638G>T	p.Arg2213Leu	missense splice_region	Exon 13 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450868 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 721902

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33226

American (AMR) AF: 0.00 AC: 0 AN: 44228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25964

East Asian (EAS) AF: 0.00 AC: 0 AN: 39410

South Asian (SAS) AF: 0.00 AC: 0 AN: 84726

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105500

Other (OTH) AF: 0.00 AC: 0 AN: 59960

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4

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

Feb 20, 2013

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 02, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with leucine 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 last nucleotide of exon 13 of the BRCA2 gene and splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies for this variant, different variants affecting the same splice donor site (c.7007G>A, c.7007G>C) have been shown to produce aberrant RNA transcripts and are considered to be disease-causing (ClinVar variation ID: 38077, 52241). It suggests that the reference sequence at this splice site is important for normal RNA splicing. This variant has been reported in individuals with personal and/or family history of breast and/or ovarian cancer (PMID: 22970155, 27157322, 28993434, 30078507, 31742824, 31782247, 35886069, Color internal data) and non-small cell lung cancer (PMID: 31565484). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Oct 05, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.7007G>T (p.Arg2336Leu) variant in exon 13 of the BRCA2 gene is the last base of exon 13 and is predicted to alter splicing resulting in a frame shift. This variant has been reported in patients with breast cancer (PMID: 22970155) and is not observed in general population databases. Other nucleotide base substitutions at this same site have also been observed to alter splicing and are considered pathogenic (PMID: 18489799, 9150172). Therefore, the c.7007G>T (p.Arg2336Leu) variant in the BRCA2 gene is classified as likely pathogenic.

not provided Pathogenic:3

Sep 10, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Located at the last nucleotide of the exon and demonstrated to result in aberrant splicing, producing multiple transcripts, including out-of-frame skipping of exons 12-13 (PMID: 33293522); Published functional studies classify this variant as non-functional based on sensitivity to PARP inhibitors (PMID: 37713444); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as 7235G>T; This variant is associated with the following publications: (PMID: 28888541, 29884841, 32377563, 22970155, 29446198, 28993434, 30078507, 31825140, 30702160, 31565484, 31782247, 31447099, 27157322, 28724667, 31742824, 33293522, 37713444, 37937776)

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Arg2336Leu variant was identified in 4 of 2798 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Kwong 2012, Kwong 2016). The variant was also identified in dbSNP (ID: rs28897743) as “With Pathogenic allele ", in ClinVar (classified as likely pathogenic by Invitae, Ambry Genetics, Color Genomics; as pathogenic by CIMBA, COGR, BIC), MutDB, LOVD 3.0 (1x as pathogenic), BIC Database (2x with clinical importance), and in ARUP Laboratories (as Definitely pathogenic). The variant was not identified in GeneInsight-COGR, Cosmic, UMD-LSDB, and Zhejiang University Database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In UMD, 2 alternate substitutions at this same nucleotide position (c.7007G>A, p.Arg2336His and c.7007G>C, p.Arg2336Pro) have been classified as causal, with evidence showing the G>A substitution causes a 70 bp deletion in exon 13 resulting in a frameshift that introduces a premature stop codon 30 codons into exon 14. Lymphocyte RT-PCR analysis showed the alternate variant c.7007G>A caused exon 13 skipping, in agreement with bionformatic studies which conclude a weakening and disruption of the splice site (Sanz 2010). A bioinformatic tool applying information theory to analyze splicing variants found the natural donor site was weakened for an alternate substitution variant (c.7007G>A), concordant with other splicing models/testing (Mucaki 2010). The p.Arg2336 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The p.Arg2336Leu variant occurs in the last three bases 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 silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

Apr 06, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In the published literature, this variant has been reported in individuals/families affected with breast and/or ovarian cancer ((PMIDs: 22970155 (2012), 27157322 (2016), 28724667 (2017), 28993434 (2018), 30078507 (2018), 31782247 (2020)), as well as non-small cell lung cancer (PMID: 31565484 (2019)). 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 disease causing or benign. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper BRCA2 mRNA splicing. This variant has not been reported in large, multi-ethnic general populations. Two other pathogenic or likely pathogenic variants affect the same amino acid. Based on the available information, this variant is classified as likely pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:2

Sep 02, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7007G>T variant (also known as p.R2336L), located in coding exon 12 of the BRCA2 gene, results from a G to T substitution at nucleotide position 7007. The amino acid change results in arginine to leucine at codon 2336, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported in individuals with breast and/or ovarian cancer, predominantly from Chinese cohorts (Kwong A et al. PLoS ONE. 2012;7(9):e43994; Wei H et al. Oncol Lett 2018 Jun;15(6):9420-9428; Li A et al. Gynecol Oncol . 2018 Oct;151(1):145-152; Bhaskaran SP et al. Int J Cancer. 2019 Aug;145(4):962-973; Cheng J et al. J Cell Mol Med. 2020 Jan;24(2):1676-1683; Gao X et al. Hum Mutat. 2020 Mar;41(3):696-708). In an assay testing BRCA2 function, this variant showed a functionally abnormal result (Sahu S et al. PLoS Genet . 2023 Sep;19(9):e1010940). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Alterations at this same position and impacting the same donor site (c.7007G>C and c.7007G>A) have been reported to result in aberrant splicing (Houdayer C et al. Hum. Mutat. 2012 Aug; 33(8):1228-38; Ambry internal data), and have been described in a compound heterozygous or homozygous state in individuals diagnosed with Fanconi anemia (Meng L et al. JAMA Pediatr. 2017 12;171(12):e173438; Ghazwani Y et al. Cancer Genet 2016 Apr;209(4):171-6). Based on the majority of available evidence to date, this variant is likely to be pathogenic. However, because variants at this location have been identified in patients with Fanconi Anemia, this alteration 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.

Aug 23, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with leucine 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 last nucleotide of exon 13 of the BRCA2 gene and splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies for this variant, different variants affecting the same splice donor site (c.7007G>A, c.7007G>C) have been shown to produce aberrant RNA transcripts and are considered to be disease-causing (ClinVar variation ID: 38077, 52241). It suggests that the reference sequence at this splice site is important for normal RNA splicing. This variant has been reported in individuals with personal and/or family history of breast and/or ovarian cancer (PMID: 22970155, 27157322, 28993434, 30078507, 31742824, 31782247, 35886069, Color internal data) and non-small cell lung cancer (PMID: 31565484). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Hereditary breast ovarian cancer syndrome Pathogenic:2

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

May 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 2336 of the BRCA2 protein (p.Arg2336Leu). This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 22970155, 27157322, 29446198, 31742824, 31825140). ClinVar contains an entry for this variant (Variation ID: 52242). 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 tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.7007 nucleotide in the BRCA2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 9150172, 21719596, 25447315). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Benign	-0.11
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.69	T
PhyloP100		4.7
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.010	N
REVEL	Uncertain	0.40
Sift	Benign	0.092	T
Sift4G	Benign	0.10	T
Vest4		0.44
MutPred		0.46		Loss of catalytic residue at R2336 (P = 0.033)
MVP		0.90
MPC		0.025
ClinPred		0.77	D
GERP RS		5.0
gMVP		0.26
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.38		Position offset: 0

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

Other links and lift over

dbSNP: rs28897743; hg19: chr13-32921033;