ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.63C>T (p.Asp21=) (rs1800369)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163241 SCV000213768 likely benign Hereditary cancer-predisposing syndrome 2014-06-18 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 RCV000196365 SCV000252723 benign Li-Fraumeni syndrome 2020-12-07 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000196365 SCV000407075 uncertain significance Li-Fraumeni syndrome 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000430891 SCV000514931 benign not specified 2015-07-31 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color Health, Inc RCV000163241 SCV000686757 likely benign Hereditary cancer-predisposing syndrome 2015-12-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590622 SCV000697443 benign not provided 2017-06-23 criteria provided, single submitter clinical testing Variant summary: The TP53 c.63C>T (p.Asp21Asp) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC in 73 of 119254 control chromosomes (2 homozygotes), but was observed exclusively in the South Asian subpopulation at a frequency of 0.004463 (73/16356; 2 homozygotes). This frequency is about 112 times the estimated maximal expected allele frequency of a pathogenic TP53 variant (0.0000398), strongly suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. The variant has been identified in breast cancer and lung cancer patients without evidence for pathogenicity (Holstege_Can Res_2009; Ginsburg_Fam Cancer_2009; Lee_JCMS_2010). Immunostaining studies in breast cancer tissue showed that TP53 was present in all cells analyzed, suggesting the variant does not affect expression (Holstege_Can Res_2009). Multiple clinical diagnostic laboratories/reputable databases have classified this variant with conflicting interpretations, including uncertain significance, likely benign and benign. Taken together, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590622 SCV001134874 benign not provided 2018-12-30 criteria provided, single submitter clinical testing
Institute of Biochemistry, Molecular Biology and Biotechnology,University of Colombo RCV001270281 SCV001450501 likely benign Familial cancer of breast criteria provided, single submitter case-control
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000590622 SCV001549707 likely benign not provided no assertion criteria provided clinical testing The TP53 p.Asp21= variant was identified in 4 of 658 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer (Ginsburg 2009, Holstege 2009, Lee 2010). The variant was also identified in dbSNP (ID: rs1800369) as "With other allele", ClinVar (classified as benign by Invitae, GeneDx, Integrated Genetics/Laboratory Corporation of America; as likely benign by Color Genomics, Ambry Genetics), and in IARC TP53 (2x). The variant was not identified in the COGR, or LOVD 3.0 databases. The variant was identified in control databases in 136 of 245170 chromosomes (2 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 136 of 30680 chromosomes (freq: 0.004), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Asp21= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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