Submissions for variant NM_000546.6(TP53):c.1079G>C (p.Gly360Ala)

gnomAD frequency: 0.00019  dbSNP: rs35993958

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000991145	SCV001142552	benign	Li-Fraumeni syndrome	2024-08-05	reviewed by expert panel	curation	The NM_000546.6: c.1079G>C variant in TP53 is a missense variant predicted to cause substitution of glycine by alanine at amino acid 360 (p.Gly360Ala). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2, Internal lab contributor: SCV000185669.8). The filtering allele frequency is 0.0005306 in the African/African American population in gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.0003 but <0.001) for BS1, and therefore meets this criterion (BS1). Computational predictor scores (BayesDel = -0.3336; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS1 BP4_Moderate. (Bayesian Points: -10; VCEP specifications version 2.0; 7/24/2024)
Ambry Genetics	RCV000130776	SCV000185669	likely benign	Hereditary cancer-predisposing syndrome	2018-09-30	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.
GeneDx	RCV000586942	SCV000211767	likely benign	not provided	2020-09-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24076587, 20182602, 12826609, 27662657, 26053092, 24729566, 19165225, 25589003, 20978130, 25318351, 16110022, 29085664, 14559903, 26580448, 28135145, 25186627, 29146883, 30352134, 30840781, 33300245)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000991145	SCV000218979	likely benign	Li-Fraumeni syndrome	2025-01-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586942	SCV000602260	benign	not provided	2020-10-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000254695	SCV000697424	likely benign	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.1079G>C (p.Gly360Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 250440 control chromosomes, predominantly at a frequency of 0.00052 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), strongly suggesting that the variant is a benign polymorphism. c.1079G>C has been reported in the literature in individuals affected with different tumor phenotypes, including colorectal cancer, acute lymphoblastic leukemia, breast cancer and osteosarcoma (e.g. Tung_2015, Yorczyk_2015, Zhang_2015, Yurgelun_2017, Qian_2018, Sheng_2019). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.2299delA, p.Ser767AlafsX25; in an internal LCA sample), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function demonstrated the variant protein to confer functional properties such as DNA binding activity, activation of target genes and induction of apoptosis that are similar to wild type TP53 (Wang_2014). 17 other submitters, including an expert panel (ClinGen TP53 Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as likely benign/benign (16x; including the expert panel) while one has classified it VUS. Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000663262	SCV000786491	likely benign	Li-Fraumeni syndrome 1	2018-05-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000586942	SCV000806232	likely benign	not provided	2017-09-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130776	SCV000910695	benign	Hereditary cancer-predisposing syndrome	2020-05-20	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000663262	SCV001431510	likely benign	Li-Fraumeni syndrome 1	2020-08-07	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000991145	SCV001439184	likely benign	Li-Fraumeni syndrome	2020-09-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586942	SCV001501155	likely benign	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000254695	SCV002070397	likely benign	not specified	2020-09-10	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225434	SCV002505058	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130776	SCV002530423	likely benign	Hereditary cancer-predisposing syndrome	2021-02-13	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149902	SCV003838423	likely benign	Breast and/or ovarian cancer	2022-05-16	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000663262	SCV004017827	uncertain significance	Li-Fraumeni syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000254695	SCV005090273	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000663262	SCV005881386	benign	Li-Fraumeni syndrome 1	2025-02-01	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130776	SCV002050315	benign	Hereditary cancer-predisposing syndrome	2021-11-09	no assertion criteria provided	clinical testing