Submissions for variant NM_000051.4(ATM):c.4306C>T (p.His1436Tyr)

gnomAD frequency: 0.00002  dbSNP: rs544891616

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167350	SCV000218202	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-08	criteria provided, single submitter	clinical testing	The p.H1436Y variant (also known as c.4306C>T), located in coding exon 28 of the ATM gene, results from a C to T substitution at nucleotide position 4306. The histidine at codon 1436 is replaced by tyrosine, an amino acid with similar properties. This alteration has been reported in at least one subject 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 alteration has also been reported in individuals diagnosed with cutaneous melanoma, breast cancer, gastric cancer and prostate cancer (Pastorino L et al. Cancers (Basel), 2020 04;12:; Akcay IM et al. Int J Cancer, 2021 01;148:285-295; Carvalho J et al. J Med Genet, 2021 01;58:1-11; Karlsson Q et al. Eur Urol Oncol, 2021 08;4:570-579). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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	RCV000229724	SCV000282956	uncertain significance	Ataxia-telangiectasia syndrome	2022-09-30	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1436 of the ATM protein (p.His1436Tyr). This variant is present in population databases (rs544891616, gnomAD 0.02%). This missense change has been observed in individual(s) with gastric cancer, melanoma, and/or prostate cancer (PMID: 32066632, 32325837, 33436325). ClinVar contains an entry for this variant (Variation ID: 187606). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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	RCV000167350	SCV000682194	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-06	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 1436 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, gastric cancer, prostate cancer, and melanoma (PMID: 28779002, 32066632, 32325837, 33436325, 33471991). In a large international case-control study, this variant was reported in 1/60465 breast cancer cases and 3/53458 controls (OR=0.295, 95%CI 0.031 to 2.833, p-value=0.347; PMID: 33471991). This variant has been identified in 8/250480 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	RCV001539145	SCV001756889	uncertain significance	not provided	2024-01-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer, prostate cancer, or melanoma (PMID: 25186627, 28779002, 32658311, 32325837, 33436325, 36555667); This variant is associated with the following publications: (PMID: 28779002, 27720647, 25186627, 28652578, 32325837, 33436325, 32066632, 36029002, 36555667, 32658311)
Baylor Genetics	RCV003468810	SCV004209545	uncertain significance	Familial cancer of breast	2023-08-27	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003468810	SCV004228245	uncertain significance	Familial cancer of breast	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1436 of the ATM protein (p.His1436Tyr). This variant is present in population databases (rs544891616, gnomAD 0.02%). This missense change has been observed in individual(s) with gastric cancer, melanoma, and/or prostate cancer (PMID: 32066632, 32325837, 33436325). ClinVar contains an entry for this variant (Variation ID: 187606). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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.
Natera, Inc.	RCV000229724	SCV001462143	uncertain significance	Ataxia-telangiectasia syndrome	2020-01-12	no assertion criteria provided	clinical testing