Submissions for variant NM_000051.4(ATM):c.946T>C (p.Tyr316His)

gnomAD frequency: 0.00006  dbSNP: rs142317485

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204232	SCV000260995	uncertain significance	Ataxia-telangiectasia syndrome	2022-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 316 of the ATM protein (p.Tyr316His). This variant is present in population databases (rs142317485, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, including male breast cancer (PMID: 28779002, 30613976). ClinVar contains an entry for this variant (Variation ID: 220453). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
Ambry Genetics	RCV000234905	SCV000273499	likely benign	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000234905	SCV000292194	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-07	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 316 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individuals affected with breast cancer but also in healthy control individuals (PMID: 28779002, 30613976, 33471991). This variant has been identified in 7/250984 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.
GeneDx	RCV000486900	SCV000567682	uncertain significance	not provided	2023-09-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history including leukemia and breast cancer as well as in unaffected controls (Athanasakis et al., 2014; Rigolin et al., 2016; Decker et al., 2017; Dorling, et al., 2021; Yang et al., 2021); This variant is associated with the following publications: (PMID: 27633522, 25587027, 28779002, 28652578, 30613976, 33471991, 34482403, 37450374)
Mendelics	RCV000204232	SCV001138442	uncertain significance	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818502	SCV002068358	uncertain significance	not specified	2021-06-14	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.946T>C, in exon 8 that results in an amino acid change, p.Tyr316His. This sequence change has been described in gnomAD with a frequency of 0.011 in the East Asian sub-population. (dbSNP rs142317485). The p.Tyr316His change affects a highly conserved amino acid residue located in a domain of the ATM protein that is known to be functional. The p.Tyr316His substitution appears to be damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in one individual with breast cancer however, it was also identified in two unaffected controls (PMID: 28779002). Due to the lack of sufficient evidences, the clinical significance of the p.Tyr316His change remains unknown at this time.
Sema4, Sema4	RCV000234905	SCV002531160	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-24	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000486900	SCV002821662	likely benign	not provided	2022-10-01	criteria provided, single submitter	clinical testing	ATM: BP1, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818502	SCV003929157	uncertain significance	not specified	2023-04-26	criteria provided, single submitter	clinical testing	Variant summary: ATM c.946T>C (p.Tyr316His) results in a 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 2.8e-05 in 250984 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.946T>C has been reported in the literature in an individual affected with breast cancer and in an individual affected with male breast cancer, but has also been reported in control individuals (e.g. Decker_2017, Rizzolo_2019). 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: 30613976, 28779002). Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=8) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003468951	SCV004212003	uncertain significance	Familial cancer of breast	2024-02-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000204232	SCV002089604	uncertain significance	Ataxia-telangiectasia syndrome	2020-07-28	no assertion criteria provided	clinical testing