Variant 13-32379878-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4

The NM_000059.4(BRCA2):c.9082G>C(p.Ala3028Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8U:1

Conservation

PhyloP100: 2.66

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 Likely_pathogenic. Variant got 7 ACMG points.

PP5

Variant 13-32379878-G-C is Pathogenic according to our data. Variant chr13-32379878-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 126199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32379878-G-C is described in Lovd as [Likely_benign].

BP4

Computational evidence support a benign effect (MetaRNN=0.35421127). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.9082G>C	p.Ala3028Pro	missense_variant	23/27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.9082G>C	p.Ala3028Pro	missense_variant	23/27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.8713G>C	p.Ala2905Pro	missense_variant	23/27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.*1140G>C		non_coding_transcript_exon_variant	22/26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000614259.2 link	n.*1140G>C		3_prime_UTR_variant	22/26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461518

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727056

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2023	Observed in an individual with triple negative breast cancer and a family history of breast and/or ovarian cancer (Wong-Brown et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 9310G>C; This variant is associated with the following publications: (PMID: 19043619, 22228431, 12228710, 34687993, 33609447, 29884841, 27273131, 34697207, 34308104, 35665744, 35736817, 25682074) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 01, 2024	The BRCA2 c.9082G>C (p.Ala3028Pro) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 25682074 (2015) and 27273131 (2016)) or Fanconi anemia with at least one case where the variant is in trans with another BRCA2 pathogenic variant (PMIDs: 34687993 (2021), 34697207 (2022), and 36721989 (2023)). Experimental studies showed that this variant has a deleterious effect in homology-directed DNA repair assays (PMIDs: 29884841 (2019), 33609447 (2021), and 35736817 (2022)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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 likely pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 04, 2023	The p.A3028P pathogenic mutation (also known as c.9082G>C), located in coding exon 22 of the BRCA2 gene, results from a G to C substitution at nucleotide position 9082. The alanine at codon 3028 is replaced by proline, an amino acid with highly similar properties. This alteration was found to segregate with disease in a family with early-onset breast cancer (Ambry internal data). In addition, this variant has been confirmed in trans with a pathogenic mutation in BRCA2 in an individual with a mild form of Fanconi anemia (Ip E et al. J Med Genet. 2022 Sep;59(9):912-915). This variant was non-functional in a homology-directed DNA repair (HDR) assay (Richardson ME et al. Am J Hum Genet. 2021 Mar;108(3):458-468). Internal structural analysis predicts that this alteration will disrupt single-stranded DNA binding (Ambry internal data). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. However, because this variant has been identified in a patient 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 02, 2023	This missense variant replaces alanine with proline at codon 3028 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). Functional studies have shown that this variant impacts BRCA2 function in homology-directed DNA repair assays (PMID: 29884841, 33609447, 35736817). This variant has been reported in three individuals affected with breast cancer (PMID: 25682074, 27273131, ClinVar: SCV000184056.9) and in the compound heterozygous state with c.4415_4418delAGAA in an individual affected with autosomal recessive Fanconi anemia (PMID: 34687993, 34697207). 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

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 3028 of the BRCA2 protein (p.Ala3028Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer or Fanconi anemia (PMID: 25682074, 27273131, 34687993, 34697207). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 126199). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 29884841, 33609447). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 16, 2023	Variant summary: BRCA2 c.9082G>C (p.Ala3028Pro) results in a non-conservative amino acid change located in the OB3 fold (IPR015188), which is part of the DNA-binding domain of the Brca2 protein (Hart_2019). Three of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 249750 control chromosomes (gnomAD). c.9082G>C has been reported in the literature in individuals affected with breast cancer (Byers_2016, Wong-Brown_2015) and other tumor phenotypes (McReynolds_2021, Kim_2021). In addition, the variant was also reported in a patient diagnosed with late-onset Fanconi anaemia, who carried a pathogenic (frame-shift) variant in trans (Ip_2022), which suggests that the variant might be a hypomorphic allele. An in vitro functional study reported that this variant results in a decreased activity in homology-directed DNA repair (HDR) assay (Hart_2018, Richardson_2021, Hu_2022). Five submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, partly without evidence for independent evaluation, and classified the variant as pathogenic (n=1) / likely pathogenic (n=1), or VUS (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Fanconi anemia complementation group D1

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Molecular Medicine, NSW Health Pathology North, Newcastle

May 17, 2017

At the time it was classified as a Variant of Unknown Significance. -

Familial cancer of breast

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 28, 2024

- -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Breast Cancer Information Core (BIC) (BRCA2)

May 29, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.051

FATHMM_MKL

Uncertain

0.86

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-0.92

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.69

N;N

REVEL

Uncertain

0.35

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0070

D;D

Vest4

0.44

MutPred

0.39

Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);

MVP

0.88

MPC

0.13

ClinPred

0.65

GERP RS

3.3

gMVP

0.68

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