NM_000059.4:c.4037_4043delCTGTTTGinsT

Variant names:

• chr13-32338392-CTGTTTG-T
• rs276174841
• NM_000059.4:c.4037_4043delCTGTTTGinsT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_000059.4(BRCA2):​c.4037_4043delCTGTTTGinsT​(p.Thr1346_Cys1348delinsIle) variant causes a missense, conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 missense, conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:12
• Conservation: PhyloP100: 0.376

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.4037_4043delCTGTTTGinsT	p.Thr1346_Cys1348delinsIle	missense_variant, 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.4037_4043delCTGTTTGinsT	p.Thr1346_Cys1348delinsIle	missense_variant, conservative_inframe_deletion	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.3668_3674delCTGTTTGinsT	p.Thr1223_Cys1225delinsIle	missense_variant, conservative_inframe_deletion	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.4037_4043delCTGTTTGinsT		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jul 10, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an in-frame deletion of three amino acids, threonine 1346, valine 1347 and cysteine 1348, and replaces them with isoleucine in the BRCA2 protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in at least one individual at risk for breast and ovarian cancer (PMID: 18418466). This variant has not been identified 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. -

May 17, 2008

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 12, 2000

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:3

Sep 15, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.4037_4043delinsT; p.Thr1346_Cys1348delinsIle variant (rs276174841), also known as 4265del7insT in the literature, is reported in at least one individual with high risk for hereditary breast and ovarian cancer (Zhou 2005). This variant is also reported in ClinVar (Variation ID: 126035). Although the p.Thr1346_Cys1348delinsIle variant is absent from the Genome Aggregation Database, the constituent variants c.4037delC and c.4039_4043delGTTTG are observed concurrently on a single allele, which indicates that it is not a common polymorphism. This variant deletes three residues and replaces them with an isoleucine, leaving the rest of the protein in-frame. Due to limited information, the clinical significance of the p.Thr1346_Cys1348delinsIle variant is uncertain at this time. References: Zhou X et al. Classification of Missense Mutations of Disease Genes. J Am Stat Assoc. 2005;100(469):51-60. PMID: 18418466. -

Oct 08, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of 3 amino acids and insertion of 1 amino acid in a non-repeat region; Observed in an individual with a personal and/or family history of breast and ovarian cancer (Zhou et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Also known as 4265_4271delCTGTTTGinsT and 4265del7insT; This variant is associated with the following publications: (PMID: 18418466) -

Jul 16, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:2

May 26, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Thr1346delinsIle variant in BRCA2 has been reported in 1 individual from a cohort of women with high risk of developing hereditary breast and ovarian canc er (Zhou 2005). It was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This variant has be en reported in ClinVar (Variation ID: 126035). This variant is an inframe deleti on of CTGTTTG and insertion T at position c.4037 and It is unclear if this delet ion/insertion will impact the protein. In summary, the clinical significance of the p.Thr1346delinsIle variant is uncertain. -

Dec 18, 2023

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.4037_4043delinsT (p.Thr1346_Cys1348delinsIle) results in an in-frame deletion-insertion that is predicted to delete three amino acids from the protein and substitute them for an Isoleucine residue. The variant was absent in 239566 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4037_4043delinsT has been reported in the literature as c.4265del7insT in at least one individual from a reportedly high-risk HBOC family with a calculated posterior probability of being deleterious of 0.46 (Zhou_2005). This report does 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 publication has been ascertained in the context of this evaluation (PMID: 18418466). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:2

Jun 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4037_4043delCTGTTTGinsT variant (also known as p.T1346_C1348delinsI), located in coding exon 10 of the BRCA2 gene, results from a deletion of 7 nucleotides and the insertion of 1 nucleotide between positions 4037 and 4043. This results in the threonine at codon 1346 being replaced by isoleucine, and the deletion of valine and cysteine residues at codons 1347 and 1348. This alteration is located in the BRC repeat domain of the BRCA2 gene, which is important for the binding of RAD51 and subsequent DNA repair. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). This nucleotide region is generally not well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

May 01, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an in-frame deletion of three amino acids, threonine 1346, valine 1347 and cysteine 1348, and replaces them with isoleucine in the BRCA2 protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in at least one individual at risk for breast and ovarian cancer (PMID: 18418466). This variant has not been identified 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. -

Familial cancer of breast Uncertain:1

Nov 12, 2022

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.4037_4043delinsT, is a complex sequence change that results in the deletion of three and insertion of 1 amino acid(s) in the BRCA2 protein (p.Thr1346_Cys1348delinsIle). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 18418466). This variant is also known as 4265del7insT. 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: rs276174841; hg19: chr13-32912529;