chr13-32363447-CAGA-C

Position:

• chr13-32363447-CAGA-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_000059.4(BRCA2):​c.8249_8251del​(p.Lys2750del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,202 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Q2749Q) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: BRCA2 NM_000059.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 8.94

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000059.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8249_8251del	p.Lys2750del	inframe_deletion	18/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8249_8251del	p.Lys2750del	inframe_deletion	18/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 32

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

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Oct 29, 2001	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Sep 07, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 27, 2016	- -

Hereditary breast ovarian cancer syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 20, 2023	This variant, c.8249_8251del, results in the deletion of 1 amino acid(s) of the BRCA2 protein (p.Lys2750del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs80359703, gnomAD 0.007%). This variant has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer (PMID: 18092194, 20567915, 28324225, 28807866, 32438681). This variant is also known as 8477delAGA or K2750delAGA. ClinVar contains an entry for this variant (Variation ID: 52537). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects BRCA2 function (PMID: 29988080). 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. -
Uncertain significance, criteria provided, single submitter	curation	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Oct 08, 2024	According to the ClinGen ENIGMA BRCA2 v1.1.0 criteria we chose this criterion: PS3 (strong pathogenic): Mesman et al 2018. Not able to complement Loss of function construct in Assay -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 06, 2019

Variant summary: BRCA2 c.8249_8251delAGA (p.Lys2750del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 3.2e-05 in 31404 control chromosomes. c.8249_8251delAGA has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Seymour_2008, Negura_2010). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed p.Lys2750del did not rescue loss-of-Brca2-mediated cell lethality (Mesman_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 13, 2020

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Also known as 8477_8479delAGA; Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Negura 2010, Meisel 2017, Santonocita 2020); Published functional studies are inconclusive: slightly reduced protein expression compared to wildtype and inability to rescue loss of BRCA2-mediated cell lethality (Mesman 2018); This variant is associated with the following publications: (PMID: 20567915, 29988080, 32438681, 28324225, 31209999, 20232139, 19941162) -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 10, 2024

The c.8249_8251delAGA variant (also known as p.K2750del) is located in coding exon 17 of the BRCA2 gene. This variant results from an in-frame AGA deletion at nucleotide positions 8249 to 8251. This results in the in-frame deletion of a lysine at codon 2750. This alteration has been detected in individuals with hereditary breast and/or ovarian cancer (Negura L et al. Fam Cancer, 2010 Dec;9:519-23; Seymour IJ et al. Breast Cancer Res. Treat. 2008 Nov;112(2):343-9; Meisel C et al. Arch Gynecol Obstet 2017 May;295(5):1227-1238, Santonocito C et al. Cancers (Basel), 2020 May;12:). This variant was found to be functionally deficient in a BRCA2-null mouse embryonic stem cell complementation assay (Mesman RLS et al. Genet Med, 2019 Feb;21:293-302). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs80359703; hg19: chr13-32937584;