Submissions for variant NM_000179.3(MSH6):c.335A>G (p.Asn112Ser)

gnomAD frequency: 0.00010  dbSNP: rs587779934

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656887	SCV000149323	uncertain significance	not provided	2024-08-02	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with endometrial, breast, or ovarian cancer, but also in unaffected controls (PMID: 29684080, 31307542, 32634176, 33471991, 36169650, 35449176); This variant is associated with the following publications: (PMID: 28292439, 23729658, 33471991, 32634176, 35449176, 36169650, 29684080, 36243179, 31422818, 31307542)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524173	SCV000166229	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115414	SCV000214649	likely benign	Hereditary cancer-predisposing syndrome	2023-03-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV000122964	SCV000430950	uncertain significance	Lynch syndrome 5	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000115414	SCV000685394	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-15	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 112 of the MSH6 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 performed for this variant. This variant has been reported in an individual affected with mismatch DNA repair proficient endometrial cancer (PMID: 31307542) and several individuals affected with breast cancer (PMID: 29684080, 33471991; Lovejoy, et al. 2018). This variant has been identified in 7/282896 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212629	SCV000731369	uncertain significance	not specified	2017-01-25	criteria provided, single submitter	clinical testing	The p.Asn112Ser variant in MSH6 has not been previously reported in individuals with Lynch syndrome. This variant has been identified in 1/10406 of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs587779934). Computational prediction tools and conservation analysis suggest that the p.Asn112Ser variant may not impact the protein, though this inf ormation is not predictive enough to rule out pathogenicity. In summary, the cli nical significance of the p.Asn112Ser variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212629	SCV001363848	uncertain significance	not specified	2019-03-27	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.335A>G (p.Asn112Ser) results in a conservative amino acid change located in the PWWP domain of 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 2.5e-05 in 277252 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.335A>G has been reported in the literature as a germline variant in two breast invasive carcinoma samples from The Cancer Genome Atlas; in one sample co-occurring with a germline pathogenic variant (ATM c.5932G>T, p.Glu1978X) (Yehia_2018). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Additional co-occurrences with other pathogenic variants have been reported (MLH1 c.116+2T>C, UMD database; MLH1 c.1489dupC, p.Arg497ProfsX6, LabCorp internal database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. One ClinVar submission indicates the variant co-occurred with a pathogenic MSH6 however variant is not provided by submitter. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656887	SCV001470566	uncertain significance	not provided	2020-08-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115414	SCV002528015	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-29	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000122964	SCV003843189	uncertain significance	Lynch syndrome 5	2023-02-15	criteria provided, single submitter	clinical testing	The MSH6 c.335A>G (p.Asn112Ser) missense change has a maximum subpopulation frequency of 0.0080% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect of this variant on protein function, but to our knowledge functional studies have not been performed. This variant has been reported in an individual with endometrial cancer who has a MSS tumor and did not meet Amsterdam criteria (PMID: 31307542). It has also been reported in an individual with a personal history of endometrial cancer, skin cancer, and no reported family history of cancer (PMID: 32634176). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Neuberg Centre For Genomic Medicine, NCGM	RCV000122964	SCV004100393	uncertain significance	Lynch syndrome 5	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense variant c.335A>G (p.Asn112Ser) in MSH6 gene has been reported previously in individuals affected with Lynch syndrome (Singh et al. 2020; Lasota et al. 2020). The p.Asn112Ser variant is present with an allele frequency of 0.002% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Benign / Likely Benign / Uncertain Significance (multiple submissions). Computational evidence (SIFT - tolerated; Polyphen - benign; MutationTaster - disease causing) predicts conflicting effect on protein structure and function for this variant. The amino acid change p.Asn112Ser in MSH6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asn at position 112 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).
All of Us Research Program, National Institutes of Health	RCV003997249	SCV004831087	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 112 of the MSH6 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 performed for this variant. This variant has been reported in an individual affected with mismatch DNA repair proficient endometrial cancer (PMID: 31307542) and several individuals affected with breast cancer (PMID: 29684080, 33471991; Lovejoy, et al. 2018). This variant has been identified in 7/282896 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115414	SCV005045442	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355172	SCV001549970	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Asn112Ser variant was identified in 1 of 460 proband chromosomes (frequency: 0.002) from individuals or families with triple negative breast cancer (Lovejoy 2018). The variant was also identified in dbSNP (ID: rs587779934) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and three other submitters), and in UMD-LSDB (1x as unclassified variant). The variant was identified in control databases in 7 of 277252 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24034 chromosomes (freq: 0.00008), European in 4 of 126734 chromosomes (freq: 0.00003), East Asian in 1 of 18868 chromosomes (freq: 0.00005), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Asn112 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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.