Submissions for variant NM_000179.3(MSH6):c.3026A>T (p.Lys1009Ile)

gnomAD frequency: 0.00003  dbSNP: rs587781593

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129648	SCV000184445	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-23	criteria provided, single submitter	clinical testing	The p.K1009I variant (also known as c.3026A>T), located in coding exon 4 of the MSH6 gene, results from an A to T substitution at nucleotide position 3026. The lysine at codon 1009 is replaced by isoleucine, an amino acid with dissimilar properties. This variant was observed in an individual diagnosed with breast cancer (Caminsky NG et al. Hum Mutat, 2016 07;37:640-52). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). Additionally, this alteration was identified in an individual with serrated polyps (Murphy A et al. J Gastroenterol Hepatol, 2022 May;37:861-869). This amino acid position is well 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.
Invitae	RCV000459156	SCV000551231	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000480608	SCV000567036	uncertain significance	not provided	2023-02-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer and serrated polyposis (Caminsky et al., 2016; Murphy et al., 2022); This variant is associated with the following publications: (PMID: 17531815, 21120944, 26898890, 35128723)
Color Diagnostics, LLC DBA Color Health	RCV000129648	SCV000690310	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-08	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with isoleucine at codon 1009 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 26898890; Murphy et al. poster#20W163, ISG 2020; Color internal data). This variant has been identified in 9/247834 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480608	SCV001470561	uncertain significance	not provided	2019-09-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315879	SCV004018624	likely benign	Lynch syndrome 5	2023-11-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726].
All of Us Research Program, National Institutes of Health	RCV003997514	SCV004834500	uncertain significance	Lynch syndrome	2023-08-28	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with isoleucine at codon 1009 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 26898890; Murphy et al. poster#20W163, ISG 2020; Color internal data). This variant has been identified in 9/247834 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354619	SCV001549280	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Lys1009Ile variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (ID: rs587781593) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and Color). The variant was identified in control databases in 9 of 242242 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5554 chromosomes (freq: 0.0002), European in 8 of 114354 chromosomes (freq: 0.00007), but not in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Lys1009 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.