chr13-32326239-C-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000059.4(BRCA2):c.476-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,613,062 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 predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 splice_region, intron

Scores

Splicing: ADA: 0.9484

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: -0.0640

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 Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.476-3C>A		splice_region_variant, intron_variant	Intron 5 of 26	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.476-3C>A	splice_region_variant, intron_variant	Intron 5 of 26	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.107-3C>A	splice_region_variant, intron_variant	Intron 5 of 26	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.476-3C>A	splice_region_variant, intron_variant	Intron 4 of 25	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152014

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:

0.000284

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251060

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135790

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:

0.000416

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461048

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726892

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:

0.000524

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152014

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74242

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:

0.000284

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:2

Jul 11, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 01, 2023

Department of Medical and Surgical Sciences, University of Bologna

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

PP3(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -

Familial cancer of breast

Uncertain:2

Jun 10, 2024

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG codes applied following ENIGMA VCEP rules: PP3 -

Aug 05, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Feb 09, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a C to A nucleotide substitution at the -3 position of intron 5 of the BRCA2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies have reported that this variant is detected with increased out-of-frame splicing predicted to cause premature truncation and an absent or non-functional protein product, albeit the splicing defect may be incomplete (PMID: 30832263, 30883759). This variant has been reported in at least two individuals affected with breast or ovarian cancer and in additional families affected with hereditary breast and ovarian cancer (PMID: 27062684, 29446198, 30078507, 30630526). This variant also has been reported in an individual diagnosed with Fanconi anemia with a pathogenic BRCA2 co-variant (PMID: 27862952). By contrast, this variant is not considered rare and has been identified in 12/282210 chromosomes (12/267726 chromosomes in the non-cancer cohort) in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease and perhaps being less penetrant than a classic loss-of-function mutation in the BRCA2 gene, additional case-control and functional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Dec 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.476-3C>A intronic variant results from a C to A substitution 3 nucleotides upstream from coding exon 5 in the BRCA2 gene. This alteration has been observed in multiple individuals and families with high risk breast and ovarian cancer (Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Li A et al. Gynecol Oncol, 2018 10;151:145-152). This variant was reported in an individual with features consistent with Fanconi Anemia (Yi, JS et al. Pediatr Blood Cancer 2017 May;64(5):). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. RNA studies have demonstrated this alteration results in an incomplete splicing in the set of samples tested; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data; Gelli E et al. Cancers (Basel), 2019 Mar;11; Fraile-Bethencourt E et al. J Pathol, 2019 08;248:409-420). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Hereditary breast ovarian cancer syndrome

Uncertain:2

Dec 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 5 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs371431745, gnomAD 0.05%). This variant has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 27062684, 29446198, 30078507, 30630526, 34026625, 35641994). ClinVar contains an entry for this variant (Variation ID: 37924). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with inconclusive levels of altered splicing (PMID: 30832263, 30883759; internal data). 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. -

Apr 02, 2025

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

According to the ClinGen ENIGMA BRCA2 v1.1.0 criteria we chose these criteria: PM3 (medium pathogenic): PMID: 27862952 (reviewed in 36721989 als VUS) 5-year-old girl with unilateral Wilms tumor (WT) and B-precursor acute lymphoblastic leukemia (ALL) chromosomal breakage revealed high levels of spontaneous breakages (56%); crosslinking agents diexpoxybutane (DEB) and mitomycin C (MMC) both induced > 330% breakage and > 3% radial formation in 25–50 metaphases seen—consistent with FA); Genetic testing revealed biallelic BRCA2/FANCD1 mutations: 888delGT and IVs5-3C>A., PP3 (supporting pathogenic): spliceAI: 0.260 (acceptor_loss), BS1 (supporting benign): gnomAD v3.1 (non-cancer): AF: 0.00002030 -

Familial pancreatic carcinoma

Uncertain:1

Apr 24, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

DANN

Benign

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.95

dbscSNV1_RF

Benign

0.65

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.26

Position offset: 3

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