Submissions for variant NM_000038.6(APC):c.1895T>C (p.Ile632Thr)

gnomAD frequency: 0.00001  dbSNP: rs587781360

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129152	SCV000183875	likely benign	Hereditary cancer-predisposing syndrome	2021-06-14	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.
GeneDx	RCV000211901	SCV000209498	uncertain significance	not provided	2023-02-16	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with a personal and/or family history of colorectal or breast and/or ovarian cancer (Yurgelun et al., 2017; Oliver et al., 2019); This variant is associated with the following publications: (PMID: 18199528, 28135145, 31921681)
Color Diagnostics, LLC DBA Color Health	RCV000129152	SCV000681493	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 632 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). This variant has been identified in 7/251340 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.
Invitae	RCV003743583	SCV001406253	uncertain significance	Familial adenomatous polyposis 1	2023-09-23	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 140904). This missense change has been observed in individual(s) with colorectal, breast, or ovarian cancer (PMID: 28135145, 31921681). This variant is present in population databases (rs587781360, gnomAD 0.01%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 632 of the APC protein (p.Ile632Thr).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778746	SCV002015116	uncertain significance	not specified	2021-10-03	criteria provided, single submitter	clinical testing	Variant summary: APC c.1895T>C (p.Ile632Thr) results in a non-conservative amino acid change in 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 2.8e-05 in 251340 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1895T>C has been reported in the literature as a VUS in settings of multigene cancer panel testing in individuals affected with colorectal or breast cancer (example, Yurgelun_2017, Oliver_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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.
Baylor Genetics	RCV002514712	SCV004201458	uncertain significance	Familial adenomatous polyposis 1	2023-07-18	criteria provided, single submitter	clinical testing