13-32394734-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_000059.4(BRCA2):c.9302T>G(p.Leu3101Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000446 in 1,613,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13U:3

Conservation

PhyloP100: 5.17

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

PP5

Variant 13-32394734-T-G is Pathogenic according to our data. Variant chr13-32394734-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.9302T>G	p.Leu3101Arg	missense_variant	Exon 25 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.9302T>G	p.Leu3101Arg	missense_variant	Exon 25 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.8933T>G	p.Leu2978Arg	missense_variant	Exon 25 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.*1360T>G		non_coding_transcript_exon_variant	Exon 24 of 26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000614259 link	n.*1360T>G		3_prime_UTR_variant	Exon 24 of 25	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000486

AC:

AN:

1461662

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000621

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

The BRCA2 p.Leu3101Arg variant was identified in dbSNP (ID: rs28897758) as â€šÃ„ÃºWith uncertain significance alleleâ€šÃ„Ã¹, Clinvitae database (classification uncertain significance), Fanconi Anemia Mutation Database (LOVD), the ClinVar database (classification uncertain significance by Invitae, Ambry Genetics, BIC and Sharing Clinical Reports Project derived from Myriad reports), GeneInsight COGR database (classification uncertain significance by 2 clinical laboratories), and the BIC database (2x with unknown clinical importance). The variant was not identified in the 1000 Genomes Project, NHLBI Exome Sequencing Project, Exome Aggregation Consortium (March 14, 2016) database, COSMIC, and LOVD IARC. The p.Leu3101 residue is not conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. One in silico study using a protein likelihood ratio, suggests that this variant is likely deleterious (Karchin 2008). However, this information is not predictive enough to assume pathogenicity, and segregation and/or additional functional studies are recommended to further elucidate the pathogenicity of this variant. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Nov 04, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 9530T>G; This variant is associated with the following publications: (PMID: 19043619, 18724707, 25859162, 28726806, 32719484, 12228710, 29884841, 37922907, 33609447, 32377563, 34326862, 33471991, 32170000, 35736817, 35665744, 31131967, 27498913) -

Jun 29, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with personal and family history of breast cancer, as well as in two fetuses (siblings) who were determined to carry an additional BRCA pathogenic variant in trans and diagnosed with Fanconi anemia (personal communication, see Kobelka, C et al., https://brca2021.ipostersessions.com/?s=B7-A7-93-51-9C-E3-B5-01-75-60-B7-01-E1-9F-65-91). In addition, an experimental study has shown this variant is damaging to BRCA2 HDR activity (PMID: 33609447 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

Mar 06, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.9302T>G; p.Leu3101Arg variant (rs28897758) is reported in the literature in an infant with fanconi anemia who carried a BRCA2 pathogenic variant presumably on the opposite allele (Dueber 2013). This variant is also reported in the ClinVar database (Variation ID: 38230). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 3101 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. REFERENCES Dueber J.C., Mosse C., Alford C.E. et al. Precursor T acute lymphoblastic leukemia from myelodysplastic syndrome in Fanconi anemia. J Hematopathol 6, 161â€“165 (2013). https://doi.org/10.1007/s12308-012-0168-2 -

Hereditary breast ovarian cancer syndrome

Pathogenic:3

Jun 10, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.9302T>G (p.Leu3101Arg) results in a non-conservative amino acid change located in the BRCA2, OB3 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250968 control chromosomes. c.9302T>G has been reported in the literature in individuals/families affected with Hereditary Breast and Ovarian Cancer (McRonald_2019), and also in individuals affected with Fanconi anemia who were reported with additional BRCA2 pathogenic variants presumed or confirmed to be in trans (Dueber_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. In an HDR assay this variant was determined to be damaging ( (Hart_2019). The following publications have been ascertained in the context of this evaluation (PMID: 19043619, 27498913, 28726806).ClinVar contains an entry for this variant (Variation ID: 38230). Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 3101 of the BRCA2 protein (p.Leu3101Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast or ovarian cancer (external communication, internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 38230). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Jul 13, 2018

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Data used in classification: The variant was observed in 10 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing was 16,600. The diagnosis of hereditary breast and/or ovarian cancer was confirmed in probands. The probands were confirmed as White British in all but two families (for which ethnicity not reported). Case control comparison against ethnically matched population data (10/16,600 in familial cases against 0/63,369 GNOMAD NFE controls) passoc=6.53x10-10 pexact= 1.49x10-7 (PS4_very strong). An additional 5 families have been identified in the UK (not included in the previous dataset).There are additional reports of this variant in ClinVar, BIC and BRCA2 LOVD. The variant is absent in the remainder of the GNOMAD populations (75,263 individuals) (PM2). In addition on testing in the UK of a fetus with a clinical diagnosis of Fanconi Anaemia D1, this variant was found in trans with a pathogenic truncating variant in BRCA2 (parental genotypes confirmed) (PM3). Predicted deleterious on AlignGVGD, SIFT, Polyphen2 HumVar (PP3). -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Apr 22, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with arginine at codon 3101 in the DNA binding/OB tower domain of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Functional studies have reported that this variant impacts BRCA2 function in homology-directed repair assays (PMID: 32377563, 35736817) and cell viability and drug sensitivity in Brca2-deficient mouse embryonic stem cells (PMID: 37922907). This variant has been detected in at least four individuals affected with breast cancer and in dozens of individuals who underwent cancer genetic testing (PMID: 32170000, 33471991; Leiden Open Variation Database DB-ID BRCA2_000444; Color internal data) and in an individual affected with sarcoma (PMID: 27498913). A multifactorial analysis has reported segregation, tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 1.1157, 3.623, 1.1293 and 0.191, respectively (PMID: 31131967). This variant also has been reported in a compound heterozygous carrier who has clinical phenotype consistent with Fanconi anemia (PMID: 33609447; ClinVar variation ID 38230). 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. -

Jan 31, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L3101R pathogenic mutation (also known as c.9302T>G), located in coding exon 24 of the BRCA2 gene, results from a T to G substitution at nucleotide position 9302. The leucine at codon 3101 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in a fetus who is compound heterozygous for this alteration and a BRCA2 frameshift mutation whose clinical features are highly suggestive of Fanconi Anemia (personal communication). In addition, this alteration was defective in a homology-directed repair assay (Ambry internal data). This variant was observed to segregate with breast cancer in multiple families (Ambry internal data). Based on internal structural assessment this alteration is expected to result in significant destabilization of OBD3, in which other destabilizing pathogenic alterations are present (Yang H et al. Science, 2002 Sep;297:1837-48). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, 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, 2

Uncertain:2

Jun 12, 2000

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

May 15, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Breast and/or ovarian cancer

Pathogenic:1

May 26, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inherited breast cancer and ovarian cancer

Pathogenic:1

Jun 26, 2024

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3,PM3 -

BRCA2-related cancer predisposition

Pathogenic:1

Jun 28, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NICE approved PARP inhibitor treatment

Pathogenic:1

Apr 24, 2024

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3,PM3 -

Familial cancer of breast

Pathogenic:1

Sep 20, 2021

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.95

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.83

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.7

N;N

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0030

D;D

Vest4

0.84

MutPred

0.83

Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);

MVP

0.98

MPC

0.18

ClinPred

0.95

GERP RS

5.9

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Other links and lift over