ClinVar Miner

Submissions for variant NM_001128425.1(MUTYH):c.37G>A (p.Ala13Thr) (rs375349172)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000199845 SCV000254711 uncertain significance MYH-associated polyposis 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 13 of the MUTYH protein (p.Ala13Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs375349172, 0.01%). This variant was reported in individuals affected with polyposis and breast cancer (PMID: 21777424, 30564557). ClinVar contains an entry for this variant (Variation ID: 216520). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). 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 RCV000216921 SCV000275777 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-11 criteria provided, single submitter clinical testing The p.A13T variant (also known as c.37G>A) is located in coding exon 2 of the MUTYH gene. The alanine at codon 13 is replaced by threonine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 2, and is predicted to weaken the efficiency of the native splice acceptor site by the BDGP and ESEfinder in silico models; however experimental evidence is not currently available. This alteration was reported in one individual from a cohort of 88 individuals with clinical features of Multiple Adenomatous Polyposis; no other MUTYH alterations were identified in this individual (Tricarico R et al. BMC Cancer, 2011;11:305). This amino acid position is not 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.
Color Health, Inc RCV000216921 SCV000685620 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-27 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 13 of the MUTYH 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 reported in a heterozygous individual affected with polyposis (PMID; 21777424) and in a male individual affected with breast cancer (PMID: 30564557). This variant has not been identified 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000502616 SCV000592672 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The p.Ala13Thr variant was identified in the literature in 1 of 156 proband chromosomes from individuals with mixed CRC phenotypes and was not identified in 20 control chromosomes (Tricarico 2011); however, this limited set of cases and controls is not sufficient to be able to predict the significance of this variant. This variant was identified by the ESP in 1 of 8600 chromsomes (frequency of 0.0001); this limited number of observations is not sufficient to determine whether or not this is a low frequency common benign variant or a rare pathogenic variant. The p.Al13 residue is not present in all mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. The p.Al13Thr (c.37G>A) variant occurs in the first base of the exon and this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, splicing in-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) does not predict a significant difference in splicing in 3 of 5 different programs. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.

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