Submissions for variant NM_001048174.2(MUTYH):c.1410G>C (p.Gln470His)

gnomAD frequency: 0.00001  dbSNP: rs587782794

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132344	SCV000187433	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-24	criteria provided, single submitter	clinical testing	The p.Q498H variant (also known as c.1494G>C), located in coding exon 15 of the MUTYH gene, results from a G to C substitution at nucleotide position 1494. The glutamine at codon 498 is replaced by histidine, an amino acid with highly similar properties. This alteration was previously reported in a 42 year-old with rectal cancer and no family history of colorectal cancer (Görgens H et al. J Mol Diagn 2006 May; 8(2):178-82). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198891	SCV000254705	uncertain significance	Familial adenomatous polyposis 2	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 498 of the MUTYH protein (p.Gln498His). This variant is present in population databases (rs587782794, gnomAD 0.002%). This missense change has been observed in individual(s) with rectal cancer (PMID: 16645203). ClinVar contains an entry for this variant (Variation ID: 142884). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	RCV000198891	SCV000792268	uncertain significance	Familial adenomatous polyposis 2	2017-06-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132344	SCV000903807	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 498 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with rectal cancer (PMID: 16645203), or thyroid cancer (PMID: 29684080). This variant has been identified in 2/242830 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.
Illumina Laboratory Services, Illumina	RCV000198891	SCV001257604	uncertain significance	Familial adenomatous polyposis 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV001558131	SCV001780016	uncertain significance	not provided	2020-07-13	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history of early-onset rectal cancer (Grgens 2006); This variant is associated with the following publications: (PMID: 24834277, 21061173, 16645203, 25525159)
Sema4, Sema4	RCV000132344	SCV002532248	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-03	criteria provided, single submitter	curation
Baylor Genetics	RCV000198891	SCV004198881	uncertain significance	Familial adenomatous polyposis 2	2023-08-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000198891	SCV004832612	uncertain significance	Familial adenomatous polyposis 2	2023-12-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 498 of the MUTYH protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with rectal cancer (PMID: 16645203), or thyroid cancer (PMID: 29684080). This variant has been identified in 2/242830 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.