Submissions for variant NM_001042492.3(NF1):c.1933A>G (p.Met645Val)

gnomAD frequency: 0.00032  dbSNP: rs146051850

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130724	SCV000185611	benign	Hereditary cancer-predisposing syndrome	2015-03-30	criteria provided, single submitter	clinical testing	Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206514	SCV000261408	benign	Neurofibromatosis, type 1	2025-02-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000286004	SCV000401721	benign	Neurofibromatosis-Noonan syndrome	2018-01-13	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000341061	SCV000401722	benign	Café-au-lait macules with pulmonary stenosis	2018-01-13	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000206514	SCV000401723	benign	Neurofibromatosis, type 1	2018-01-13	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000301396	SCV000401724	benign	Neurofibromatosis, familial spinal	2018-01-13	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000680336	SCV000521060	benign	not provided	2018-04-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000680336	SCV000884239	benign	not provided	2024-08-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121627	SCV000917896	benign	not specified	2018-12-27	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.1933A>G (p.Met645Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 301926 control chromosomes (gnomAD and publication), predominantly at a frequency of 0.017 within the East Asian subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 81.59 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 phenotype (0.00021), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1933A>G has been reported in the literature in individuals affected with Neurofibromatosis Type 1 and male breast cancer without strong evidence for causality while, two of the studies report co-occurrence of the variant with other causative variants (c.3211G>C; c.910C>T (classified pathogenic in ClinVar); c.162_163insAT; other nonsense mutations) (Momozawa_2018, Pasmant_2015, Zhang_2015, Xu_2014, Ko_2013). Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign (3x) and once as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000206514	SCV001140347	benign	Neurofibromatosis, type 1	2019-05-28	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000206514	SCV001478993	benign	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130724	SCV002527430	benign	Hereditary cancer-predisposing syndrome	2020-12-16	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000206514	SCV002561113	benign	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492433	SCV002795894	likely benign	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2021-12-28	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000301396	SCV004016418	benign	Neurofibromatosis, familial spinal	2023-07-07	criteria provided, single submitter	clinical testing
ITMI	RCV000121627	SCV000085825	not provided	not specified	2013-09-19	no assertion provided	reference population