ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.4964C>A (p.Ser1655Tyr)

gnomAD frequency: 0.00003  dbSNP: rs786201215
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163104 SCV000213613 likely benign Hereditary cancer-predisposing syndrome 2021-09-15 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.
GeneDx RCV000486511 SCV000566497 uncertain significance not provided 2017-10-27 criteria provided, single submitter clinical testing This variant is denoted ATM c.4964C>A at the cDNA level, p.Ser1655Tyr (S1655Y) at the protein level, and results in the change of a Serine to a Tyrosine (TCC>TAC). This variant was identified in an unaffected 44 year old female who underwent multi-gene cancer panel testing, and also harbored a CDH1 truncating variant (Huynh 2016). ATM Ser1655Tyr was not observed in large population cohorts (Lek 2016). Since Serine and Tyrosine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Ser1655Tyr occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether ATM Ser1655Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000804749 SCV000944672 uncertain significance Ataxia-telangiectasia syndrome 2024-01-10 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 1655 of the ATM protein (p.Ser1655Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer and/or melanoma (PMID: 30374176, 34326862). ClinVar contains an entry for this variant (Variation ID: 184002). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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.
Color Diagnostics, LLC DBA Color Health RCV000163104 SCV001344861 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-27 criteria provided, single submitter clinical testing This missense variant replaces serine with tyrosine at codon 1655 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251008 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 RCV002228686 SCV002511596 uncertain significance not specified 2022-04-11 criteria provided, single submitter clinical testing Variant summary: ATM c.4964C>A (p.Ser1655Tyr) 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 251008 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4964C>A has been reported in the literature to co-occur with a CDH1 pathogenic variant (c.187C>T, p.Arg63X) in a 44 year old unaffected woman and her unaffected mother (Huynh_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: all classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV002485008 SCV002792858 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2021-07-27 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV004589698 SCV005081961 likely benign Familial cancer of breast 2024-05-21 criteria provided, single submitter clinical testing This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Natera, Inc. RCV000804749 SCV002078329 uncertain significance Ataxia-telangiectasia syndrome 2020-10-05 no assertion criteria provided clinical testing

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