NM_001354689.3(RAF1):c.212A>G (p.Asn71Ser) AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Benign(1);Uncertain significance(1) (Last evaluated: Jul 27, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000037686.5

Allele description [Variation Report for NM_001354689.3(RAF1):c.212A>G (p.Asn71Ser)]

NM_001354689.3(RAF1):c.212A>G (p.Asn71Ser)

Gene:
RAF1:Raf-1 proto-oncogene, serine/threonine kinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p25.2
Genomic location:
Preferred name:
NM_001354689.3(RAF1):c.212A>G (p.Asn71Ser)
Other names:
p.N71S:AAT>AGT; NM_002880.3(RAF1):c.212A>G
HGVS:
  • NC_000003.12:g.12612058T>C
  • NG_007467.1:g.57122A>G
  • NM_001354689.3:c.212A>GMANE SELECT
  • NM_001354690.2:c.212A>G
  • NM_001354691.2:c.78-2723A>G
  • NM_001354692.2:c.78-2723A>G
  • NM_001354693.2:c.212A>G
  • NM_001354694.2:c.78-2723A>G
  • NM_001354695.2:c.78-2723A>G
  • NM_002880.3:c.212A>G
  • NP_001341618.1:p.Asn71Ser
  • NP_001341619.1:p.Asn71Ser
  • NP_001341622.1:p.Asn71Ser
  • NP_002871.1:p.Asn71Ser
  • LRG_413t1:c.212A>G
  • LRG_413t2:c.212A>G
  • LRG_413:g.57122A>G
  • LRG_413p1:p.Asn71Ser
  • LRG_413p2:p.Asn71Ser
  • NC_000003.11:g.12653557T>C
  • NR_148940.2:n.543A>G
  • NR_148941.2:n.543A>G
  • NR_148942.2:n.543A>G
  • c.212A>G
Protein change:
N71S
Links:
dbSNP: rs184022679
NCBI 1000 Genomes Browser:
rs184022679
Molecular consequence:
  • NM_001354691.2:c.78-2723A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354692.2:c.78-2723A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354694.2:c.78-2723A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354695.2:c.78-2723A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354689.3:c.212A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354690.2:c.212A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354693.2:c.212A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002880.3:c.212A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_148940.2:n.543A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148941.2:n.543A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148942.2:n.543A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
1

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000061348Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Uncertain significance
(Jan 16, 2013)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000698125Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Benign
(Jul 27, 2021)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided11not providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000061348.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

Variant classified as Uncertain Significance - Favor Benign. The Asn71Ser varian t in RAF1 has not been previously reported in the literature nor previously been identified by our laboratory. This variant has been identified in 0.01% (1/8600 ) of European American chromosomes from a broad population by the NHLBI Exome Se quencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs184022679). Computa tional analyses (biochemical amino acid properties, conservation, AlignGVGD, Pol yPhen2, and SIFT) suggest that the Asn71Ser variant may not impact the normal fu nction of the protein, though this information is not predictive enough to rule out pathogenicity. Of note, the Shrew (a species in the Mammalian class) also ca rries a serine (Ser) at amino acid position 71 in the RAF1 gene. In summary, add itional information is needed to fully assess the clinical significance of this variant.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698125.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Variant summary: RAF1 c.212A>G (p.Asn71Ser) results in a conservative amino acid change located in the Raf-like Ras-binding (IPR003116) 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 0.00025 in 251492 control chromosomes, predominantly at a frequency of 0.0014 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 56 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAF1 causing Noonan Syndrome and Related Conditions phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.212A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Four other ClinVar submitters (evaluation after 2014) including an expert panel (ClinGen RASopathy Variant Curation Expert Panel) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Aug 27, 2021

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