13-32379477-T-G

Position:

chr13-32379477-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000059.4(BRCA2):c.8915T>G(p.Leu2972Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,613,234 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2972F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:1

Conservation

PhyloP100: 6.36

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.8915T>G	p.Leu2972Trp	missense_variant	22/27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.8915T>G	p.Leu2972Trp	missense_variant	22/27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.8546T>G	p.Leu2849Trp	missense_variant	22/27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.*973T>G		non_coding_transcript_exon_variant	21/26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000614259 link	n.*973T>G		3_prime_UTR_variant	21/25	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152172

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

GnomAD3 exomes

AF:

0.0000321

AC:

AN:

249366

Hom.:

AF XY:

0.0000445

AC XY:

AN XY:

134856

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:

0.0000711

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461062

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726784

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000171

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

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

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:3Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Jan 17, 2001	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 21, 2023	This missense variant replaces leucine with tryptophan at codon 2972 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant has a partial or no impact on BRCA2 function in homology-mediated repair assays (PMID: 29394989, 35736817) and inconclusive impact on sensitivity to PARP inhibitors (PMID: 32444794). This variant has been reported in at least three individuals affected with breast and/or ovarian cancer, two individuals affected with prostate cancer, and at least seven unaffected individuals (PMID: 29752822, 32438681, 32853339, 33471991; Leiden Open Variation Database DB-ID BRCA2_000383). This variant has been identified in 8/249366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Jul 17, 2024	The following ACMG criteria is used: BS1_Supporting; BP4 (BayesDel score 0.12), BS3 (PMID: 38417439) -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jun 19, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2015	This variant is denoted BRCA2 c.8915T>G at the cDNA level, p.Leu2972Trp (L2972W) at the protein level, and results in the change of a Leucine to a Tryptophan (TTG>TGG). Using alternate nomenclature, this variant would be defined as BRCA2 9143T>G. This variant has been included in one functional study where it was determined not to influence the interaction with Filamin A (Mondal 2012). BRCA2 Leu2972Trp was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Leucine and Tryptophan differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Leu2972Trp occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is located within the DNA binding domain (Borg 2010). Both in house in silico analyses and published computational models predict that this variant is probably damaging to protein structure and function (Karchin 2008). Based on currently available information, it is unclear whether BRCA2 Leu2972Trp is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 20, 2023	In the published literature, this variant has been reported in individuals with a personal history of breast and/or ovarian cancer (PMID: 32438681 (2020), 31227342 (2019)), or prostate cancer (PMID: 32853339 (2021)), or at high risk of hereditary breast cancer (PMID: 29752822 (2018)). In a large scale breast cancer association study, the variant was observed in breast cancer cases as well as unaffected control individuals (PMID: 33471991 (2021)). Experimental studies have demonstrated this variant has a neutral (PMID: 35736817 (2022), 22771033 (2012)) or intermediate (PMID: 29394989 (2018)) effect on BRCA2 protein function. The frequency of this variant in the general population, 0.000071 (8/112520 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 14, 2022	Variant summary: BRCA2 c.8915T>G (p.Leu2972Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249366 control chromosomes (gnomAD). c.8915T>G has been reported in the literature in individuals affected with breast- and/or ovarian cancer (e.g. Santonocito_2020, Li_2019) and prostate cancer (e.g. Darst_2021). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 3/60466 cases, but was also found in 7/53461 controls (Dorling_2021 through LOVD). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant had a partial effect on homology directed DNA repair activity (Guidugli_2018), but resulted in filamin A binding activity to the wild-type(Mondal_2012). Four ClinVar submitters have assessed the variant since 2014: all four classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 05, 2023	This missense variant replaces leucine with tryptophan at codon 2972 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant has a partial or no impact on BRCA2 function in homology-mediated repair assays (PMID: 29394989, 35736817) and inconclusive impact on sensitivity to PARP inhibitors (PMID: 32444794). This variant has been reported in at least three individuals affected with breast and/or ovarian cancer, two individuals affected with prostate cancer, and at least seven unaffected individuals (PMID: 29752822, 32438681, 32853339, 33471991; Leiden Open Variation Database DB-ID BRCA2_000383). This variant has been identified in 8/249366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 25, 2023	The p.L2972W variant (also known as c.8915T>G), located in coding exon 21 of the BRCA2 gene, results from a T to G substitution at nucleotide position 8915. The leucine at codon 2972 is replaced by tryptophan, an amino acid with similar properties. This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Li JY et al. Int J Cancer, 2019 Jan;144:281-289; Santonocito C et al. Cancers (Basel), 2020 May;12:). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 13, 2023

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 2972 of the BRCA2 protein (p.Leu2972Trp). This variant is present in population databases (rs80359142, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, and/or prostate cancer (PMID: 29752822, 32438681, 32853339). ClinVar contains an entry for this variant (Variation ID: 52700). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 22771033). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Benign

0.96

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.97

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.70

D;D

MetaSVM

Uncertain

0.45

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.8

N;N

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Vest4

0.65

MVP

0.97

MPC

0.19

ClinPred

0.78

GERP RS

5.5

gMVP

0.78

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