Submissions for variant NM_000051.4(ATM):c.8187A>C (p.Gln2729His)

gnomAD frequency: 0.00002  dbSNP: rs587781946

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130316	SCV000185166	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-22	criteria provided, single submitter	clinical testing	The p.Q2729H variant (also known as c.8187A>C), located in coding exon 55 of the ATM gene, results from an A to C substitution at nucleotide position 8187. The glutamine at codon 2729 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a male patient diagnosed with breast cancer (Fostira F et al. Breast Cancer Res. Treat., 2018 May;169:105-113). This alteration has also been reported in 1/191 men with a personal and family history of prostate cancer (Leongamornlert D et al. Br. J. Cancer, 2014 Mar;110:1663-72). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549269	SCV000622806	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 2729 of the ATM protein (p.Gln2729His). This variant is present in population databases (rs587781946, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer and/or prostate cancer (PMID: 24556621, 29335925, 35127508, 35264596, 35534704). ClinVar contains an entry for this variant (Variation ID: 141700). 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.
Counsyl	RCV000549269	SCV000791122	uncertain significance	Ataxia-telangiectasia syndrome	2017-04-28	criteria provided, single submitter	clinical testing
Mendelics	RCV000549269	SCV000838608	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130316	SCV000904747	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-22	criteria provided, single submitter	clinical testing
GeneDx	RCV001576209	SCV001803347	uncertain significance	not provided	2023-04-20	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 breast or prostate cancer (Leongamornlert et al., 2014; Fostira et al., 2018; Andrikopoulou et al., 2022; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 29678143, 25148578, 24556621, 29335925, 30814645, 35127508, 23532176, 15279808, 35226061, 35264596)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398761	SCV004122430	uncertain significance	not specified	2023-10-31	criteria provided, single submitter	clinical testing	Variant summary: ATM c.8187A>C (p.Gln2729His) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251036 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8187A>C has been reported in the literature in individuals with multiple cancer types, without evidence of causality, including breast Cancer (e.g. Guindalini_2022, Andrikopoulou_2021) male breast cancer (e.g. Fostira_2018), prostate cancer (e.g. Leongamornlert_2014, Karlsson_2021), melanoma (e.g. Dalmasso_2021), colorectal cancer (e.g. Randon_2019), chronic lymphocytic leukemia or other hemoatological malignancy (e.g. Lampson_2023), without cancer but with cancer family history (e.g. deOlivera_2022), and conversely, in control cohorts without a cancer phenotype (e.g. Tiao_2015, Karlsson_2021). These report(s) 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: 35127508, 34262154, 29335925, 35264596, 33436325, 36315919, 24556621, 30814645, 28652578, 35534704). Six 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.
Baylor Genetics	RCV004567110	SCV005057138	uncertain significance	Familial cancer of breast	2023-12-19	criteria provided, single submitter	clinical testing