Submissions for variant NM_000051.4(ATM):c.4304A>C (p.Lys1435Thr)

gnomAD frequency: 0.00003  dbSNP: rs769980220

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168111	SCV000218767	likely benign	Ataxia-telangiectasia syndrome	2023-12-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000220668	SCV000273136	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-21	criteria provided, single submitter	clinical testing	The p.K1435T variant (also known as c.4304A>C), located in coding exon 28 of the ATM gene, results from an A to C substitution at nucleotide position 4304. The lysine at codon 1435 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in at least one breast cancer patient in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000478130	SCV000566002	uncertain significance	not provided	2018-09-28	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.4304A>C at the cDNA level, p.Lys1435Thr (K1435T) at the protein level, and results in the change of a Lysine to a Threonine (AAG>ACG). This variant has been observed in breast cancer cases as well as an unaffected control (Decker 2017). ATM Lys1435Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This very is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Lys1435Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000220668	SCV000682193	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-11	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with threonine at codon 1435 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer and in an unaffected individual (PMID: 28779002). In a large international case-control study, this variant was reported in 3/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 1/250358 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780906	SCV000918545	uncertain significance	not specified	2023-08-08	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4304A>C (p.Lys1435Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250358 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4304A>C has been reported in the literature in individuals affected with Breast Cancer or hematologic malignancies including chronic lymphocytic leukemia without strong evidence for causality (example, Dorling_2021, Lampson_2023). This variant has also been reported in a publication but is unclear whether it was observed in controls and/or Breast Cancer patients (Decker_2017). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. 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: 28779002, 36315919, 33471991). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=5; Likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000220668	SCV002534634	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-17	criteria provided, single submitter	curation
Baylor Genetics	RCV003468825	SCV004210246	uncertain significance	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000168111	SCV001462142	uncertain significance	Ataxia-telangiectasia syndrome	2020-01-10	no assertion criteria provided	clinical testing