ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.5488A>G (p.Met1830Val)

gnomAD frequency: 0.00001  dbSNP: rs587781622
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129712 SCV000184515 likely benign Hereditary cancer-predisposing syndrome 2018-11-23 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 RCV000199250 SCV000254121 likely benign Ataxia-telangiectasia syndrome 2024-01-24 criteria provided, single submitter clinical testing
GeneDx RCV000590655 SCV000292471 uncertain significance not provided 2023-03-22 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, but also in controls (Momozawa et al., 2018; Yehia et al., 2018); This variant is associated with the following publications: (PMID: 27034805, 26667234, 29684080, 30287823, 32566746)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002307401 SCV000694303 likely benign not specified 2022-10-21 criteria provided, single submitter clinical testing Variant summary: ATM c.5488A>G (p.Met1830Val) 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 1.2e-05 in 250794 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5488A>G in individuals affected with Ataxia-Telangiectasia/ATM-related cancers and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (MSH6 c.1767del , p.Pro591fs), providing supporting evidence for a benign role. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with with conflicting assessments (likely benign, n=3; VUS, n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health RCV000129712 SCV000910899 likely benign Hereditary cancer-predisposing syndrome 2016-01-04 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000590655 SCV001143114 uncertain significance not provided 2019-05-17 criteria provided, single submitter clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research RCV001030597 SCV001193482 uncertain significance Hereditary breast ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000590655 SCV002010806 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003430705 SCV004118580 uncertain significance ATM-related condition 2023-04-04 criteria provided, single submitter clinical testing The ATM c.5488A>G variant is predicted to result in the amino acid substitution p.Met1830Val. This variant has been reported with uncertain significance in individuals with breast cancer or Cowden syndome (Supplemental Data 2 in Momozawa et al. 2018. PubMed ID: 30287823; Table S9 in Yehia et al. 2018. PubMed ID: 29684080). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108173748-A-G), and has classifications of both uncertain and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141271). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001357265 SCV001552684 uncertain significance Familial pancreatic carcinoma no assertion criteria provided clinical testing The ATM p.Met1830Val variant was identified in 8 of 21,054 proband chromosomes (frequency: 0.0004) from individuals with breast and pancreatic cancer and was present in 13 of 47,462 control chromosomes (frequency: 0.0003) from healthy individuals (Momozawa 2018, Yehia 2018). The variant was identified in dbSNP (rs587781622) as “with uncertain significance allele”, ClinVar (interpreted as "uncertain significance" by Invitae and 2 others, "likely benign" by Ambry Genetics and 1 other) and LOVD 3.0 (observed 3x). The variant was identified in control databases in 3 of 245578 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5470 chromosomes (freq: 0.0002), European in 1 of 111,200 chromosomes (freq: 0.000009), East Asian in 1 of 17,234 chromosomes (freq: 0.00006), while the variant was not observed in the African, Latino, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Met1830 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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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