Submissions for variant NM_000038.6(APC):c.7018A>C (p.Asn2340His)

gnomAD frequency: 0.00002  dbSNP: rs748940586

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485956	SCV000565844	uncertain significance	not provided	2023-11-09	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; This variant is associated with the following publications: (PMID: 32992489, 18199528, 25559809)
Color Diagnostics, LLC DBA Color Health	RCV000582404	SCV000687107	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-02	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with histidine at codon 2340 of the APC protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with colon cancer (PMID: 25559809). This variant has been identified in 4/250218 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	RCV003651918	SCV000768176	uncertain significance	Familial adenomatous polyposis 1	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 2340 of the APC protein (p.Asn2340His). This variant is present in population databases (rs748940586, gnomAD 0.004%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 25559809). ClinVar contains an entry for this variant (Variation ID: 418637). 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.
Ambry Genetics	RCV000582404	SCV001188213	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-25	criteria provided, single submitter	clinical testing	The p.N2340H variant (also known as c.7018A>C), located in coding exon 15 of the APC gene, results from an A to C substitution at nucleotide position 7018. The asparagine at codon 2340 is replaced by histidine, an amino acid with similar properties. This variant was observed in 1/626 individuals with early-onset familial colorectal cancer cases, who had germline genetic testing for colon cancer associated genes; this 55 year old female had proximal colon cancer and a maternal aunt with colorectal cancer at age 62 (Chubb D et al. J. Clin. Oncol. 2015 Feb; 33(5):426-32). This alteration was also reported in a cohort of elderly cancer-free individuals (Zheng G et al. Cancers (Basel), 2020 Sep;12:). This amino acid position is well 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.