Submissions for variant NM_000038.6(APC):c.7402T>C (p.Ser2468Pro)

gnomAD frequency: 0.00004  dbSNP: rs375586273

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163734	SCV000214309	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-16	criteria provided, single submitter	clinical testing	The p.S2468P variant (also known as c.7402T>C), located in coding exon 15 of the APC gene, results from a T to C substitution at nucleotide position 7402. The serine at codon 2468 is replaced by proline, an amino acid with similar properties. This alteration was detected on a 25-gene panel test in a woman of Western/Northern European ancestry with a personal history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). This alteration was also reported in conjunction with a PMS2 truncating mutation in a patient with endometrial cancer diagnosed at age 50 and MSI-H, MSH6-absent ascending colorectal cancer diagnosed at age 80. This individual did not have colon polyps and met Amsterdam criteria (Rohlin A et al. Fam. Cancer. 2017 Apr;16:195-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV003743609	SCV000282820	uncertain significance	Familial adenomatous polyposis 1	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 2468 of the APC protein (p.Ser2468Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 184474). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl	RCV000234737	SCV000487829	uncertain significance	Familial adenomatous polyposis 1	2015-12-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163734	SCV000687125	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces serine with proline at codon 2468 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with breast cancer (PMID: 25186627) and in an individual affected with colorectal cancer, who also carried a pathogenic PMS2 variant that could explain the observed phenotype (PMID: 27696107). This variant has been identified in 3/245882 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000234737	SCV000890908	uncertain significance	Familial adenomatous polyposis 1	2021-08-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779738	SCV000916509	uncertain significance	not specified	2021-06-28	criteria provided, single submitter	clinical testing	Variant summary: APC c.7402T>C (p.Ser2468Pro) results in a non-conservative amino acid change located in the adenomatous polyposis coli protein basic domain (IPR009234) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251118 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7402T>C has been reported in the literature in an individual affected with breast cancer (Tung 2014), however this report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. Co-occurrence with another pathogenic variant has been reported in a colorectal carcinoma patient (Rohlin 2016: PMS2 c.861_864delACAG, p.Arg287fsX19), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV001310857	SCV001500828	uncertain significance	not provided	2020-08-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163734	SCV002527601	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-17	criteria provided, single submitter	curation
GeneDx	RCV001310857	SCV002757742	uncertain significance	not provided	2022-11-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colon and other others (Tung et al., 2015; Rohlin et al., 2017); This variant is associated with the following publications: (PMID: 27696107, 25186627)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000779738	SCV002760366	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003316005	SCV004018719	uncertain significance	Familial adenomatous polyposis 1	2023-02-17	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.
PreventionGenetics, part of Exact Sciences	RCV003398835	SCV004105691	uncertain significance	APC-related condition	2023-09-27	criteria provided, single submitter	clinical testing	The APC c.7402T>C variant is predicted to result in the amino acid substitution p.Ser2468Pro. This variant was reported in an individual with breast cancer (Tung et al. 2015. PubMed ID: 25186627). It was also seen along with PMS2 c.861_864del in an individual with endometrial cancer at age 50 and colorectal cancer at age 80 (Rohlin et al. 2017. PubMed ID: 27696107). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-112178693-T-C) and is reported as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/184474/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000234737	SCV004198923	uncertain significance	Familial adenomatous polyposis 1	2023-10-11	criteria provided, single submitter	clinical testing