Submissions for variant NM_001042492.3(NF1):c.181A>G (p.Ile61Val)

gnomAD frequency: 0.00004  dbSNP: rs754295034

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000539139	SCV000628390	benign	Neurofibromatosis, type 1	2025-01-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002316492	SCV000670363	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-10-30	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.
GeneDx	RCV001562458	SCV001785221	likely benign	not provided	2019-07-22	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30287823)
PreventionGenetics, part of Exact Sciences	RCV004553182	SCV004120812	uncertain significance	NF1-related disorder	2022-09-01	criteria provided, single submitter	clinical testing	The NF1 c.181A>G variant is predicted to result in the amino acid substitution p.Ile61Val. This variant was reported in an individual with Breast cancer, female (Momozawa et al 2018. PubMed ID: 30287823, Supplementary Data 1). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-29483121-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987586	SCV004803552	uncertain significance	not specified	2024-01-22	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.181A>G (p.Ile61Val) results in a conservative amino acid change in 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 1.6e-05 in 251188 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To the best of our knowledge, c.181A>G has not been reported in the literature in individuals affected with Neurofibromatosis Type 1. Three recent case-control studies of Breast cancer and Biliary tract cancer did not found this variant in the disease cohorts but reported in the controls (example, Momozawa_2018, Okawa_2023, Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1 and other NF1-related disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30287823, 36243179, 33471991). ClinVar contains an entry for this variant (Variation ID: 457548). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.