Submissions for variant NM_000059.4(BRCA2):c.4037_4043delinsT (p.Thr1346_Cys1348delinsIle)

dbSNP: rs276174841

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130011	SCV000184836	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-26	criteria provided, single submitter	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.
Invitae	RCV000229550	SCV000283224	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-05	criteria provided, single submitter	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). This variant is not present in population databases (gnomAD no frequency). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000508118	SCV000605778	uncertain significance	not specified	2017-05-26	criteria provided, single submitter	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759609	SCV000889036	uncertain significance	not provided	2021-07-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130011	SCV000906469	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-01	criteria provided, single submitter	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000508118	SCV000916933	uncertain significance	not specified	2023-12-18	criteria provided, single submitter	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.
GeneDx	RCV000759609	SCV001825723	uncertain significance	not provided	2023-10-08	criteria provided, single submitter	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)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000759609	SCV003799746	uncertain significance	not provided	2022-09-15	criteria provided, single submitter	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.
Baylor Genetics	RCV003474699	SCV004210454	uncertain significance	Familial cancer of breast	2022-11-12	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113263	SCV000146360	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2000-06-12	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113263	SCV000297525	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2008-05-17	no assertion criteria provided	clinical testing