13-32339571-ATTTAAG-A

Variant names:

• chr13-32339571-ATTTAAG-A
• rs397507775
• NM_000059.4:c.5218_5223delTTAAGT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_000059.4(BRCA2):​c.5218_5223delTTAAGT​(p.Leu1740_Ser1741del) variant causes a conservative 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1740L) 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 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1
• 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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5218_5223delTTAAGT	p.Leu1740_Ser1741del	conservative_inframe_deletion	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.5218_5223delTTAAGT	p.Leu1740_Ser1741del	conservative_inframe_deletion	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.4849_4854delTTAAGT	p.Leu1617_Ser1618del	conservative_inframe_deletion	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.5218_5223delTTAAGT		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

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

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 248722 AF XY: 0.0000297

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33306

American (AMR) AF: 0.00 AC: 0 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39614

South Asian (SAS) AF: 0.0000467 AC: 4 AN: 85620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108850

Other (OTH) AF: 0.00 AC: 0 AN: 60192

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

African (AFR) AF: 0.00 AC: 0 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5204

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Dec 16, 2015

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Feb 20, 2013

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:2

Nov 30, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.5218_5223del (p.Leu1740_Ser1741del) variant has been reported in the published literature in individuals who were at high-risk breast and/or ovarian cancer (PMID: 18779604 (2008), 22970155 (2012)), and in individuals with breast cancer (PMID: 28664449 (2017), 38003901 (2023)), gastric cancer (PMID: 36627197 (2023)), and thoratic cancer (PMID: 36964191 (2023)). The frequency of this variant in the general population, 0.0003 (6/19916 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -

Dec 12, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:1 Benign:1

Sep 05, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Uncertain:1

May 02, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.5218_5223delTTAAGT (p.Leu1740_Ser1741del) results in an in-frame deletion that is predicted to remove two amino acids from the encoded protein. The variant allele was found at a frequency of 2.8e-05 in 250239 control chromosomes (gnomad v2 Database, Chian_2021). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5218_5223delTTAAGT has been observed in individuals affected with breast cancer, gastric cancer, or thoracic cancer without strong evidence for causality (e.g. Kwong_2012, Kurian_2008, Kwong_2016, Li_2017, Zhang_2023, Tsang_2023, Sukpan_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34235180, 18779604, 22970155, 27157322, 28664449, 38003901, 36964191, 36627197). ClinVar contains an entry for this variant (Variation ID: 51824). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Aug 08, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=26/174	disease causing (fs/PTC)

Splicing

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

Publications

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Other links and lift over

dbSNP: rs397507775; hg19: chr13-32913708;