Submissions for variant NM_000051.4(ATM):c.2630G>C (p.Ser877Thr)

gnomAD frequency: 0.00001  dbSNP: rs370269552

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211985	SCV000149070	likely benign	not provided	2019-03-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19781682, 26689913, 30093976)
Ambry Genetics	RCV000115161	SCV000184961	likely benign	Hereditary cancer-predisposing syndrome	2018-03-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV001083203	SCV000219104	benign	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115161	SCV000910866	benign	Hereditary cancer-predisposing syndrome	2015-09-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174578	SCV001337756	uncertain significance	not specified	2020-01-10	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2630G>C (p.Ser877Thr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251400 control chromosomes in the gnomAD database, including 1 homozygote. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2630G>C has been reported in the literature in individuals affected with Breast Cancer and lung cancer as well as in controls (Bernstein_2010, Chan_2018, Lu_2015, Parry_2017, Tavtigian_2009). These reports 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (3x benign/likely benign, 1x VUS). Based on the evidence outlined above, the variant was classified as uncertain significance.
MGZ Medical Genetics Center	RCV002288588	SCV002579607	uncertain significance	Familial cancer of breast	2021-10-25	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000211985	SCV001548706	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ATM p.Ser877Thr variant was identified in 3 of 5062 proband chromosomes (frequency: 0.0006) from individuals or families with breast cancer and was present in 3 of 4490 control chromosomes (frequency: 0.0007) from healthy individuals (Tavtigian 2009). The variant was also identified in the following databases: dbSNP (ID: rs370269552) as "With Uncertain significance allele", ClinVar (1x likely benign, 2x uncertain significance), and Clinvitae. The variant was not identified in COGR, Cosmic, MutDB, LOVD 3.0, or the ATM-LOVD database. The variant was identified in control databases in 9 of 246196 chromosomes (1 homozygous) at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Other in 1 of 5484 chromosomes (freq: 0.0002), European in 1 of 111666 chromosomes (freq: 0.000009), East Asian in 4 of 17238 chromosomes (freq: 0.0002), and South Asian in 3 of 30780 chromosomes (freq: 0.0001). The variant was not observed in the African, Latino, Ashkenazi Jewish, or Finnish populations. The p.Ser877 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000211985	SCV001977657	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000211985	SCV001979393	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000211985	SCV002036529	likely benign	not provided		no assertion criteria provided	clinical testing