rs397507775

chr13-32339571-ATTTAAG-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4

The NM_000059.4(BRCA2):c.5218_5223del(p.Leu1740_Ser1741del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000621 in 1,609,336 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. Y1739Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: BRCA2 NM_000059.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 1.73

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 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000059.4.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.5218_5223del	p.Leu1740_Ser1741del	inframe_deletion	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.5218_5223del	p.Leu1740_Ser1741del	inframe_deletion	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152232 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: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000241 AC: 6 AN: 248722 Hom.: 0 AF XY: 0.0000297 AC XY: 4 AN XY: 134578

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0000333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1457104 Hom.: 0 AF XY: 0.00000828 AC XY: 6 AN XY: 724960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000467

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74388

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 16, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2013	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 23, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2022	In-frame deletion of 2 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Identified in individuals with breast cancer or other history meeting BRCA1/2 testing criteria, but also reported in individuals without a personal history of cancer (Kwong et al., 2012; Kurian et al., 2008; Li et al., 2017; Dong et al., 2021); Also known as 5446_5451delTTAAGT; This variant is associated with the following publications: (PMID: 28664449, 26635394, 22970155, 18779604, 27157322, 28726806, 26187060, 30702160, 31825140, 32467295) -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 20, 2024	The c.5218_5223delTTAAGT variant (also known as p.L1740_S1741del) is located in coding exon 10 of the BRCA2 gene. This variant results from an in-frame TTAAGT deletion at nucleotide positions 5218 to 5223. This results in the in-frame deletion of a at codon 1740. This alteration has been reported in high-risk breast and/or ovarian cancer patients, predominantly of Asian descent (Kurian AW et al. J. Clin. Oncol. 2008 Oct;26(29):4752-8; Kwong A et al. PLoS One. 2012; 7(9):e43994; Li G et al. J. Cancer Res. Clin. Oncol. 2017 Oct;143(10):2011-2024; Bhaskaran SP et al. Int J Cancer, 2019 08;145:962-973; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Sukpan P et al. J Pers Med, 2023 Nov;13). These deleted amino acids are not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 19, 2022	This variant causes an in-frame deletion of 2 amino acids at codon 1740 and 1741 of the BRCA2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 3 individuals affected with breast cancer or ovarian cancer (PMID: 18779604, 28664449, DOI: 10.1515) and 1 family affected with breast and/or ovarian cancer (PMID: 22970155). This variant has been identified in 7/280116 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Leu1740_Ser1741del variant was identified in 1 of 1302 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Kwong 2012). The variant was also identified in dbSNP (ID: rs757271988) as “NA”, the ClinVar database (as Uncertain Significance by Invitae, Ambry, BIC, and GeneDx), ARUP Laboratories BRCA Mutations Database (definitely pathogenic), GeneInsight COGR database (VUS by two clinical laboratories), and UMD (3x as unclassified variant). This variant has been identified by our laboratory twice, both time is Asian individuals with a medical or family history suggestive of a predisposition to breast cancer. The variant is located within a repetitive region of the BRCA2 protein that has been shown to be a binding site for RAD51 however it is unclear if this deletion would disrupt such protein binding (Buisson 2014 24485656). The variant was identified control databases in the Exome Aggregation consortium (Aug 8 2016) and the Genome Aggregation Database (Oct 3, 2017) in 7 of 274938 chromosomes (freq. 0.00003). Specifically the variant was observed in the East Asian population in 6 of 18834 chromosomes (freq. 0.0003) and in South Asians in 1 of 30140 (freq. 0.00003) while the variant was not observed in the European Non-Finnish, Ashkenazi Jewish, “Other”, African, Latino or Finnish populations. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. This variant is an in-frame deletion resulting in the removal of a Leucine and a Serine residue at codons 1740 and 1741; the impact of this alteration on BRCA2 protein function is not known. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 08, 2023

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

This variant, c.5218_5223del, results in the deletion of 2 amino acid(s) of the BRCA2 protein (p.Leu1740_Ser1741del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs757271988, gnomAD 0.03%). This variant has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 22970155, 26187060, 31825140). ClinVar contains an entry for this variant (Variation ID: 51824). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397507775; hg19: chr13-32913708;