Submissions for variant NM_000051.4(ATM):c.4910A>G (p.Asp1637Gly)

dbSNP: rs763457172

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456711	SCV000546736	likely benign	Ataxia-telangiectasia syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000571141	SCV000672696	likely benign	Hereditary cancer-predisposing syndrome	2021-03-31	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.
GeneKor MSA	RCV000571141	SCV000821858	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000571141	SCV000910873	likely benign	Hereditary cancer-predisposing syndrome	2016-05-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000571141	SCV002535487	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-10	criteria provided, single submitter	curation
Athena Diagnostics	RCV002473013	SCV002771646	uncertain significance	not provided	2022-03-17	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003230499	SCV003926640	uncertain significance	Familial cancer of breast	2023-05-30	criteria provided, single submitter	clinical testing	a variant of uncertain significance was detected in the ATM gene (Asp1637Gly). This sequence change replaces aspartic acid with glycine at codon 1637 of the ATM protein (p.Asp1637Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs763457172, ExAC 0.08%). This variant has been observed in an individual affected with breast and/or ovarian cancer in a study of 1000 indian families (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 407499) with 4 submissions: 1 benign and 3 variant of uncertain significance. In-silico predictions show benign computational verdict based on 11 benign predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI and SIFT vs 1 pathogenic prediction from FATHMM-MKL and the position is not strongly conserved. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Therefore, it has been classified as a Variant of Uncertain Significance. Heterozygous pathogenic/likely pathogenic mutations in the ATM gene are associated with susceptibility to breast cancer (OMIM 114480 ).
Neuberg Centre For Genomic Medicine, NCGM	RCV003230499	SCV004047830	uncertain significance	Familial cancer of breast		criteria provided, single submitter	clinical testing	The missense variant c.4910A>G (p.Asp1637Gly) has been submitted to ClinVar as a Variant of Uncertain Significance (VUS). This variant has been observed in an individual affected with breast and/or ovarian cancer (Singh J et al). This p.Asp1637Gly variant has allele frequency of 0.011% in the gnomAD and novel (not in any individuals) in 1000 genome database. The amino acid Asp at position 1637 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Asp1637Gly in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance (VUS).
Baylor Genetics	RCV003230499	SCV004207757	uncertain significance	Familial cancer of breast	2024-02-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000456711	SCV004234541	uncertain significance	Ataxia-telangiectasia syndrome	2023-02-28	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV003230499	SCV004565364	uncertain significance	Familial cancer of breast	2024-02-06	criteria provided, single submitter	clinical testing	A heterozygous splice site proximal missense variation in exon 33 of the ATM gene that results in the amino acid substitution of Glycine for Aspartic Acid at codon 1637 (p.Asp1637Gly) was detected. The observed variation has previously been reported in breast and/or ovarian cancer patients [PMID: 29470806, 30093976]. The p.Asp1637Gly variant has not been reported in the 1000 genomes database and has a minor allele frequency of 0.005% in the gnomAD database. The in-silico predictions of the variant are benign by PolyPhen-2 (Hum_Div), SIFT, LRT and Mutation Taster2 tools. The reference codon is conserved in mammals. In summary, the variant meets our criteria to be classified as a variant of uncertain significance.
Natera, Inc.	RCV000456711	SCV001462151	uncertain significance	Ataxia-telangiectasia syndrome	2020-01-04	no assertion criteria provided	clinical testing