rs587782878

Variant names:

• chr13-32379742-CCAAA-C
• rs587782878
• NM_000059.4:c.8954-5_8954-2delAACA

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PVS1_Moderate BP6

The NM_000059.4(BRCA2):​c.8954-5_8954-2delAACA variant causes a splice acceptor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,608,620 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: BRCA2 NM_000059.4 splice_acceptor, splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 3.23

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.01598908 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.8, offset of 0 (no position change), new splice context is: tctttctcatctttctccAGtta. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 13-32379742-CCAAA-C is Benign according to our data. Variant chr13-32379742-CCAAA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38199.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=6, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8954-5_8954-2delAACA		splice_acceptor_variant, splice_region_variant, intron_variant	Intron 22 of 26	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8954-7_8954-4delCAAA		splice_region_variant, intron_variant	Intron 22 of 26	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8585-7_8585-4delCAAA		splice_region_variant, intron_variant	Intron 22 of 26	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1012-7_*1012-4delCAAA		splice_region_variant, intron_variant	Intron 21 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

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: 0.000108 AC: 27 AN: 250478 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135374

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00147

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1456502 Hom.: 0 AF XY: 0.0000304 AC XY: 22 AN XY: 724786

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000858

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152118 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74308

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00115

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000680

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:2

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 17, 2015

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:3

Dec 06, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jun 21, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified Benign:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 21, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.8954-5_8954-2delAACA alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 281868 control chromosomes, predominantly at a frequency of 0.0015 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.8954-5_8954-2delAACA, has been reported in the literature in individuals affected with breast cancer but without evidence for causality (Carney_2010, Chan_2018, Lai_2017, Suter_2004). In addition, co-occurrences with pathogenic BRCA2 variant have been reported (c.7878G>A, p.Trp2626X; Carney_2010, LabCorp internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS (n=2), Benign (n=2)). Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

Jul 15, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31825140) -

Jun 21, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1

Sep 20, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related disorder Benign:1

Sep 11, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.8954-5_8954-2delAACA was identified in the literature in an individual with breast cancer. However in the same patient a co-occurring pathogenic BRCA2 variant (p.Trp2626X) was identified, increasing the likelihood that the c.8954-5_8954-2delAACA variant may not have clinical significance (Carney 2010). The variant was also identified in the Clinvar database (classified as likely benign by the Sharing Clinical Reports Project (SCRP) (derived from Myriad reports); classified as likely benign by Ambry Genetics). The c.8954-5_8954-2delAACA variant occurs within the invariant dinucleotide AG sequence (at positions -2 to -1) within the 3’ splice region. Although the deletion affects the -2 nucleotide (adenine, or A), the four base-pair deletion (AACA) results in a sequence with an adenine (A) at the -2 position, thus preserving the invariant AG donor sequence. Positions -3 and -5 to 12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. The variant sequence resulting from the 4 base-pair deletion is different from the wild-type sequence within this region, thus splicing may be affected. In silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a change to the donor splice site; however this information is not predictive enough to rule out pathogenicity.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 benign role for this variant. This variant is classified as likely benign. -

Hereditary breast ovarian cancer syndrome Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs587782878; hg19: chr13-32953879;