Submissions for variant NM_001048174.2(MUTYH):c.631G>A (p.Val211Ile)

gnomAD frequency: 0.00004  dbSNP: rs759295912

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167374	SCV000218227	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-19	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). 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 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	Familial adenomatous polyposis 2	2016-04-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409405	SCV000639353	uncertain significance	Familial adenomatous polyposis 2	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 239 of the MUTYH protein (p.Val239Ile). This variant is present in population databases (rs759295912, gnomAD 0.02%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 28961279, 32068069). This variant is also known as p.Val225Ile. ClinVar contains an entry for this variant (Variation ID: 187628). 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.
Color Diagnostics, LLC DBA Color Health	RCV000167374	SCV000685662	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-20	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 individuals affected with breast cancer (PMID: 28961279, 32068069). 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	Familial adenomatous polyposis 2	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000993997	SCV001982663	uncertain significance	not provided	2021-10-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Sung 2017); Also reported as p.(Val225Ile); This variant is associated with the following publications: (PMID: 11801590, 23108399, 28961279)
Mayo Clinic Laboratories, Mayo Clinic	RCV000993997	SCV002542108	uncertain significance	not provided	2021-12-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226228	SCV003922785	uncertain significance	not specified	2023-03-17	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.715G>A (p.Val239Ile) results in a conservative amino acid change located in the HhH-GPD domain (IPR003265) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250556 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.715G>A has been reported in the literature in individuals affected with breast cancer or pancreatic cancer (Sung_2017, Kwong_2020, Zhu_2021). These reports do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000409405	SCV004198831	uncertain significance	Familial adenomatous polyposis 2	2023-10-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000409405	SCV004841426	uncertain significance	Familial adenomatous polyposis 2	2023-12-13	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 individuals affected with breast cancer (PMID: 28961279, 32068069). 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.
GenomeConnect - Invitae Patient Insights Network	RCV000409405	SCV001749576	not provided	Familial adenomatous polyposis 2		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.