ClinVar Miner

Submissions for variant NM_001048171.1(MUTYH):c.673G>A (p.Val225Ile) (rs759295912)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167374 SCV000218227 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-09 criteria provided, single submitter clinical testing The p.V239I variant (also known as c.715G>A), located in coding exon 9 of the MUTYH gene, results from a G to A substitution at nucleotide position 715. The valine at codon 239 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was identified in one individual from a Taiwanese HBOC cohort (Sung PL et al. PLoS ONE, 2017 Sep;12:e0185615). This amino acid position is highly 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.
Counsyl RCV000409405 SCV000487346 uncertain significance MYH-associated polyposis 2016-04-13 criteria provided, single submitter clinical testing
Invitae RCV000409405 SCV000639353 uncertain significance MYH-associated polyposis 2020-10-04 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 239 of the MUTYH protein (p.Val239Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs759295912, ExAC 0.03%). This variant has been observed in trans (on the opposite chromosome) from a pathogenic variant in MUTYH in an individual affected with an unrelated cancer (Invitae). Considering that biallelic pathogenic variants are expected to be found in an individual affected with MUTYH-associated polyposis, this evidence indicates that this variant is not a primary cause of disease. Also, this variant has been reported in an individual affected with breast cancer (PMID: 28961279). This variant is also known as p.Val225Ile in the literature. ClinVar contains an entry for this variant (Variation ID: 187628). 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 C2). 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. 5
Color Health, Inc RCV000167374 SCV000685662 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-28 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 239 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 breast cancer (PMID: 28961279). This variant has been identified in 8/281912 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 RCV000409405 SCV001135257 uncertain significance MYH-associated polyposis 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000993997 SCV001147268 uncertain significance not provided 2018-09-01 criteria provided, single submitter clinical testing
GenomeConnect - Invitae Patient Insights Network RCV000409405 SCV001749576 not provided MYH-associated polyposis no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 09-11-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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