ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.901G>A (p.Val301Met) (rs147718169)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129011 SCV000172908 likely benign Hereditary cancer-predisposing syndrome 2020-07-07 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Other strong data
Invitae RCV000205715 SCV000260639 uncertain significance MYH-associated polyposis 2020-10-23 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 329 of the MUTYH protein (p.Val329Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs147718169, ExAC 0.03%). This variant has been observed to be homozygous or hemizygous in an individual who was not affected with MUTYH-associated polyposis (Invitae). ClinVar contains an entry for this variant (Variation ID: 134859). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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.
GeneDx RCV000656910 SCV000292628 uncertain significance not provided 2018-08-28 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.985G>A at the cDNA level, p.Val329Met (V329M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). Using alternate nomenclature, this variant has also been published as MUTYH Val315Met or Val326Met. This variant was observed in the heterozygous state in individuals with a Lynch-associated cancer and/or polyps, head/neck squamous cell carcinoma, breast cancer, or sarcoma (Ricci 2016, Gorgens 2007, Ballinger 2016, Yurgelun 2015, Tung 2015). MUTYH Val329Met was also identified in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. MUTYH Val329Met was observed at an allele frequency of 0.015% (5/34,420) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is located in the 9-1-1 binding domain (Shi 2006, Luncsford 2010). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MUTYH Val329Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two MUTYH pathogenic variants on opposite chromosomes.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000121592 SCV000297028 uncertain significance not specified 2015-07-27 criteria provided, single submitter clinical testing
Counsyl RCV000205715 SCV000487343 uncertain significance MYH-associated polyposis 2016-03-29 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515294 SCV000611408 uncertain significance MYH-associated polyposis; Pilomatrixoma; Neoplasm of stomach 2017-05-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129011 SCV000685684 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-28 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 329 of the MUTYH protein. This variant is also known as c.943G>A (p.Val315Pro) based on an alternative transcript (NM_001048171). 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 individuals affected with head and neck cancer, colorectal cancer, and breast cancer cancer in the literature (PMID: 17207658, 25186627, 25980754, 27829682, 31062380). This variant has also been identified in 23/282826 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.
Mendelics RCV000205715 SCV000837757 uncertain significance MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656910 SCV000889536 uncertain significance not provided 2019-08-26 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121592 SCV000919793 uncertain significance not specified 2018-02-26 criteria provided, single submitter clinical testing Variant summary: MUTYH c.985G>A (p.Val329Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-05 in 277224 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (8.3e-05 vs 4.60e-03), allowing no conclusion about variant significance. The c.985G>A variant has been reported in the literature in individuals affected with MUTYH-associated Polyposis (Yurgelun_2015, Ricci_2016) . 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ITMI RCV000121592 SCV000085788 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000656910 SCV000592703 uncertain significance not provided no assertion criteria provided clinical testing The MUTYH p.Val329Met variant was identified in 4 of 3176 proband chromosomes (frequency: 0.0013) in one individual with squamous cell carcinoma of the head and neck (Gorgens 2007), two individuals with MUTYH-associated polyposis (Ricci 2017) and one individual with Lynch syndrome (Yurgelun 2015). The variant was also identified in dbSNP (ID: rs147718169) as “With Uncertain significance, other allele”, ClinVar (uncertain significance by Ambry Genetics, Invitae, GeneDx, Children's Hospital of Philadelphia, Counsyl, Fulgent Genetics, and Color), Clinvitae (4x), and Insight Colon Cancer Gene Variant Database. The variant was not identified in Cosmic, MutDB, or UMD-LSDB databases. The variant was also identified by our laboratory in 1 individual with Lynch Syndrome. The variant was identified in control databases in 23 of 277164 chromosomes at a frequency of 0.00008 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24018 chromosomes (freq: 0.00008), Other in 1 of 6466 chromosomes (freq: 0.0002), Latino in 5 of 34420 chromosomes (freq: 0.0001), European (Non-Finnish) in 12 of 126662 chromosomes (freq: 0.0001), and South Asian in 3 of 30782 chromosomes (freq: 0.0001), while the variant was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The p.Val329 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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 uncertain significance.

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