ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3727A>T (p.Thr1243Ser) (rs147453999)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588959 SCV000149328 uncertain significance not provided 2018-08-01 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3727A>T at the cDNA level, p.Thr1243Ser (T1243S) at the protein level, and results in the change of a Threonine to a Serine (ACA>TCA). This variant has been observed in individuals with ovarian cancer or mesothelioma (Pal 2012, Betti 2017), and was detected by whole exome sequencing in an individual with developmental delay, autism, and some dysmorphic features, with no specific information about cancer history (Wang 2015). MSH6 Thr1243Ser was observed at an allele frequency of 0.1% (35/30,782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Thr1243Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV001081954 SCV000166233 likely benign Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115419 SCV000186076 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-08 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Illumina Clinical Services Laboratory,Illumina RCV000122966 SCV000430979 uncertain significance Lynch syndrome 2016-06-14 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000212687 SCV000592654 uncertain significance not specified 2016-03-23 criteria provided, single submitter clinical testing
Color RCV000115419 SCV000685435 likely benign Hereditary cancer-predisposing syndrome 2020-03-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588959 SCV000695885 likely benign not provided 2016-07-18 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3727A>T (p.Thr1243Ser) variant causes a missense change involving a conserved nucleotide with 3/5 in silico tools predicting a "damaging" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 34/121216 (1/3565), predominantly in the South Asian cohort, 19/16504 (1/868), which exceeds the estimated maximal expected allele frequency for a pathogenic MSH6 variant of 1/7037. Therefore, suggesting that the variant is a common polymorphism found in population(s) of South Asian origin. A publication has cited the variant in an affected individual, although with limited information (ie, lack of co-occurrence or co-segregation). Multiple reputable databases/clinical laboratories cite the variant with conflicting classifications "uncertain significance" or "likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Likely Benign."
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659895 SCV000781793 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-11-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000588959 SCV000805896 uncertain significance not provided 2017-03-27 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115419 SCV000822067 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000659895 SCV001135846 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000115419 SCV000788052 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-27 no assertion criteria provided clinical testing
Center of Medical Genetics and Primary Health Care RCV001005027 SCV000987278 uncertain significance bilateral breast cancer 2020-04-08 no assertion criteria provided research ACMG Guidelines 2015 criteria PM1 Pathogenic Moderate: A domain mutATP5 (V1127-1321R aa) functioning in ATPase activity. Hot-spot has 30 non-VUS coding variants (19 pathogenic and 11 benign), pathogenicity = 63.3%, proximity score 9.180 > threshold 2.472. PP3 Pathogenic Supporting: 7 pathogenic predictions from DEOGEN2, FATHMM-MKL, M-CAP, MVP, MutationTaster, PrimateAI and SIFT vs 4 benign predictions from DANN, EIGEN, MutationAssessor and REVEL. BS1 Benign Strong: GnomAD exomes South Asian allele frequency = 0.00114 > 0.000649 derived from the 3,884 clinically reported variants in gene MSH6 of which 739 PATH, 2,198 VUS and 947 benign. BP1 Benign Supporting: 85 out of 114 non-VUS missense variants in gene MSH6 are BEN = 74.6% > threshold of 51.0%, and 947 out of 3,884 clinically reported variants in gene MSH6 are BEN = 24.4% > threshold of 24.0%. BP6: Multiple reputable databases/clinical laboratories cite the variant with conflicting classifications "uncertain significance" or "likely benign." Therefore, it has been classified as a Variant of Uncertain Significance.

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