Submissions for variant NM_000179.3(MSH6):c.1661G>A (p.Arg554His)

gnomAD frequency: 0.00004  dbSNP: rs730881791

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000767214	SCV000211278	uncertain significance	not provided	2020-07-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160668	SCV000601512	uncertain significance	not specified	2017-03-21	criteria provided, single submitter	clinical testing
Invitae	RCV000560061	SCV000624677	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000571101	SCV000669891	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-04	criteria provided, single submitter	clinical testing	The p.R554H variant (also known as c.1661G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 1661. The arginine at codon 554 is replaced by histidine, an amino acid with highly similar properties. This alteration was detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This alteration was also seen in 1/732 breast cancer patients, 0/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). 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.
Color Diagnostics, LLC DBA Color Health	RCV000571101	SCV000690215	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 554 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 reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 10/250818 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	RCV000708869	SCV000837884	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000767214	SCV001152292	uncertain significance	not provided	2017-02-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000160668	SCV003839751	uncertain significance	not specified	2022-07-14	no assertion criteria provided	clinical testing	DNA sequence analysis of the MSH6 gene demonstrated a sequence change, c.1661G>A, in exon 4 that results in an amino acid change, p.Arg554His. This sequence change does not appear to have been previously described in individuals with MSH6-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.016% in the South Asian subpopulation (dbSNP rs730881791). The p.Arg554His change affects a moderately conserved amino acid residue located in a domain of the MSH6 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg554His substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg554His change remains unknown at this time.