rs587782878

Positions:

• chr13-32379742-CCAAA-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_000059.4(BRCA2):​c.8954-5_8954-2del variant causes a splice region, splice polypyrimidine tract, 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_region, splice_polypyrimidine_tract, 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 Likely_benign. Variant got -1 ACMG points.

• 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: {Benign=6, Uncertain_significance=1, Likely_benign=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8954-5_8954-2del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8954-5_8954-2del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_000059.4	ENSP00000369497	A2

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

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 17, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 04, 2011	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 06, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2014	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

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 21, 2019	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

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2015	This variant is associated with the following publications: (PMID: 31825140) -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Sep 20, 2022

- -

BRCA2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 11, 2023

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

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

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;