ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2630G>C (p.Ser877Thr) (rs370269552)

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Total submissions: 6
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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 Co-occurence with mutation in same gene (phase unknown);in silico models in agreement (benign)
Invitae RCV001083203 SCV000219104 benign Ataxia-telangiectasia syndrome 2020-12-07 criteria provided, single submitter clinical testing
Color Health, Inc 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.
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.

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