Submissions for variant NM_000051.4(ATM):c.4329C>A (p.His1443Gln)

gnomAD frequency: 0.00008  dbSNP: rs377065665

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164709	SCV000215377	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-07	criteria provided, single submitter	clinical testing	The p.H1443Q variant (also known as c.4329C>A), located in coding exon 28 of the ATM gene, results from a C to A substitution at nucleotide position 4329. The histidine at codon 1443 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is 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.
Illumina Laboratory Services, Illumina	RCV000307354	SCV000367053	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000307354	SCV000546709	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1443 of the ATM protein (p.His1443Gln). This variant is present in population databases (rs377065665, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 31871109). ClinVar contains an entry for this variant (Variation ID: 185311). 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 tolerated. 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.
GeneDx	RCV000521912	SCV000616645	uncertain significance	not provided	2023-07-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Eygelaar et al., 2022); This variant is associated with the following publications: (PMID: 31871109, 36452878, 33471991, 35039564)
Color Diagnostics, LLC DBA Color Health	RCV000164709	SCV000687541	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-19	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 1443 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 8/282294 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	RCV001824649	SCV002074304	uncertain significance	not specified	2024-01-08	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4329C>A (p.His1443Gln) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250910 control chromosomes, predominantly at a frequency of 6.2e-05 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, c.4329C>A has not been reported in the literature in individuals affected with Ataxia-Telangiectasia and 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: 31871109, 33471991). ClinVar contains an entry for this variant (Variation ID: 185311). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004552895	SCV004115326	uncertain significance	ATM-related disorder	2022-10-21	criteria provided, single submitter	clinical testing	The ATM c.4329C>A variant is predicted to result in the amino acid substitution p.His1443Gln. This variant has been reported in multiple individuals with breast cancer (Adedokun et al 2020. PubMed ID: 31871109; Eygelaar et al 2022. PubMed ID: 35039564). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108160421-C-A). This variant has been interpreted as uncertain by multiple groups in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/185311). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003467304	SCV004209480	uncertain significance	Familial cancer of breast	2023-09-09	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000307354	SCV001458206	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing