Submissions for variant NM_000546.6(TP53):c.63C>T (p.Asp21=)

dbSNP: rs1800369

Total submissions: 12

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: 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196365	SCV000252723	benign	Li-Fraumeni syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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 Diagnostics, LLC DBA Color Health	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	2023-06-20	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
Sema4, Sema4	RCV000163241	SCV002530473	benign	Hereditary cancer-predisposing syndrome	2021-03-04	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000430891	SCV002760892	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492674	SCV004239789	likely benign	Breast and/or ovarian cancer	2023-05-19	criteria provided, single submitter	clinical testing
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.