Submissions for variant NM_001048174.2(MUTYH):c.916C>G (p.Pro306Ala)

gnomAD frequency: 0.00002  dbSNP: rs587778537

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162642	SCV000213079	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-24	criteria provided, single submitter	clinical testing	The p.P334A variant (also known as c.1000C>G), located in coding exon 12 of the MUTYH gene, results from a C to G substitution at nucleotide position 1000. The proline at codon 334 is replaced by alanine, an amino acid with highly similar properties. This alteration has previously been detected in an individual with greater than 10 colon polyps (Guarinos C, Clin. Cancer Res. 2014 Mar; 20(5):1158-68), and was also detected in 1/1231 colorectal cancer patients and 0/93 controls (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This alteration was identified in 2/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This variant was also reported in 5/60,466 breast cancer cases and in 5/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is poorly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476756	SCV000545705	uncertain significance	Familial adenomatous polyposis 2	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 334 of the MUTYH protein (p.Pro334Ala). This variant is present in population databases (rs587778537, gnomAD 0.006%). This missense change has been observed in individual(s) with multiple adenomatous and serrated polyps (PMID: 24470512). ClinVar contains an entry for this variant (Variation ID: 183823). 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.
Fulgent Genetics, Fulgent Genetics	RCV000765174	SCV000896407	uncertain significance	Familial adenomatous polyposis 2; Pilomatrixoma; Neoplasm of stomach	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162642	SCV000903809	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 334 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 an individual affected with multiple adenomatous and serrated polyps (PMID: 24470512). In a large international case-control study, this variant was reported in 5/60466 breast cancer cases and 5/53461 controls (PMID: 33471991). This variant has been identified in 3/228910 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780497	SCV000917801	uncertain significance	not specified	2018-03-30	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1000C>G (p.Pro334Ala) results in a non-conservative amino acid change in the encoded protein sequence that lies 3 nucleotides away from an exon-intron junction. Four of five in-silico tools predict a benign effect of the variant on protein function. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.3e-05 in 224868 control chromosomes. This frequency is not higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (1.3e-05 vs 0.0046), allowing no conclusion about variant significance. c.1000C>G has been reported in the literature in individuals affected with MUTYH-associated Polyposis. However, these reports do not provide unequivocal conclusions about an association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237746	SCV002011074	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162642	SCV002532195	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-30	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000476756	SCV002579086	uncertain significance	Familial adenomatous polyposis 2	2022-07-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000476756	SCV003817137	uncertain significance	Familial adenomatous polyposis 2	2019-06-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000476756	SCV004835159	uncertain significance	Familial adenomatous polyposis 2	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 334 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 an individual affected with multiple adenomatous and serrated polyps (PMID: 24470512). In a large international case-control study, this variant was reported in 5/60466 breast cancer cases and 5/53461 controls (PMID: 33471991). This variant has been identified in 3/228910 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	RCV003237746	SCV005385862	uncertain significance	not provided	2024-04-26	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 an individual with colonic polyps (PMID: 24470512); This variant is associated with the following publications: (PMID: 24470512, 16879101, 20816984, 33471991, 28135145, 28944238, 29641532)