Submissions for variant NM_000038.6(APC):c.4332A>T (p.Gln1444His)

dbSNP: rs748342378

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003535737	SCV000552774	uncertain significance	Familial adenomatous polyposis 1	2023-07-24	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: 411562). This missense change has been observed in individual(s) with clinical features of APC-related conditions (PMID: 25980754). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1444 of the APC protein (p.Gln1444His).
Ambry Genetics	RCV000571742	SCV000667243	likely benign	Hereditary cancer-predisposing syndrome	2023-03-07	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.
Color Diagnostics, LLC DBA Color Health	RCV000571742	SCV000903927	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 1444 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 performed for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has also been identified in 2/251194 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.
GeneDx	RCV001550235	SCV001770531	uncertain significance	not provided	2023-02-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with Lynch syndrome-associated cancer and/or polyps (Yurgelun et al., 2015); This variant is associated with the following publications: (PMID: 25742471, 30309722, 18199528, 25980754)
Sema4, Sema4	RCV000571742	SCV002532015	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-13	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002489079	SCV002782650	uncertain significance	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2022-05-31	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002526464	SCV004175617	uncertain significance	Familial adenomatous polyposis 1	2023-02-09	criteria provided, single submitter	clinical testing	The APC c.4332A>T variant is classified as VUS. The APC c.4332A>T variant is a single nucleotide change in exon 16/16 of the APC gene, which is predicted to change the amino acid glutamine at position 1444 in the protein to histidine. This variant was reported in an individual that had a history of Lynch syndrome-associated cancer (PMID: 25980754) Disease causing variants in APC are predominantly truncating variants and this variant is a missense variant which is not located in the first 15-amino acid repeat of the β-catenin binding domain (codon 1021-1035) (BP1). The variant has been reported in dbSNP (rs748342378) and in the HGMD database: CM1825341. It has been reported as Uncertain significance by other diagnostic laboratories (ClinVar Variation ID: 411562).