7-140924603-GCGGCGCCGGCGC-GCGGCGCCGGCGCCGGCGC

Variant names:

• chr7-140924603-G-GCGGCGC
• rs397507458
• NM_001374258.1:c.95_100dupGCGCCG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_004333.6(BRAF):​c.95_100dupGCGCCG​(p.Gly32_Ala33dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,528,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: BRAF NM_004333.6 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.0760

Genes affected

BRAF (HGNC:1097): (B-Raf proto-oncogene, serine/threonine kinase) This gene encodes a protein belonging to the RAF family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene, most commonly the V600E mutation, are the most frequently identified cancer-causing mutations in melanoma, and have been identified in various other cancers as well, including non-Hodgkin lymphoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia and adenocarcinoma of lung. Mutations in this gene are also associated with cardiofaciocutaneous, Noonan, and Costello syndromes, which exhibit overlapping phenotypes. A pseudogene of this gene has been identified on the X chromosome. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 7-140924603-G-GCGGCGC is Benign according to our data. Variant chr7-140924603-G-GCGGCGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41448.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000284 (43/151504) while in subpopulation EAS AF= 0.000595 (3/5042). AF 95% confidence interval is 0.000242. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.95_100dupGCGCCG	p.Gly32_Ala33dup	conservative_inframe_insertion	Exon 1 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.95_100dupGCGCCG	p.Gly32_Ala33dup	conservative_inframe_insertion	Exon 1 of 18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.95_100dupGCGCCG	p.Gly32_Ala33dup	conservative_inframe_insertion	Exon 1 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.95_100dupGCGCCG	p.Gly32_Ala33dup	conservative_inframe_insertion	Exon 1 of 18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes AF: 0.000284 AC: 43 AN: 151504 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000595

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000339

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000792 AC: 10 AN: 126314 Hom.: 0 AF XY: 0.0000578 AC XY: 4 AN XY: 69262

Gnomad AFR exome AF: 0.000173

Gnomad AMR exome AF: 0.0000415

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000978

Gnomad SAS exome AF: 0.0000450

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000856

Gnomad OTH exome AF: 0.000510

GnomAD4 exome AF: 0.000165 AC: 227 AN: 1377364 Hom.: 0 Cov.: 32 AF XY: 0.000160 AC XY: 109 AN XY: 679562

Gnomad4 AFR exome AF: 0.0000965

Gnomad4 AMR exome AF: 0.000142

Gnomad4 ASJ exome AF: 0.0000400

Gnomad4 EAS exome AF: 0.000197

Gnomad4 SAS exome AF: 0.0000760

Gnomad4 FIN exome AF: 0.0000299

Gnomad4 NFE exome AF: 0.000188

Gnomad4 OTH exome AF: 0.0000348

GnomAD4 genome AF: 0.000284 AC: 43 AN: 151504 Hom.: 0 Cov.: 31 AF XY: 0.000243 AC XY: 18 AN XY: 73984

Gnomad4 AFR AF: 0.000387

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000595

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000339

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jul 11, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 33297573) -

Mar 18, 2013

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy Uncertain:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.95_100dup, results in the insertion of 2 amino acid(s) of the BRAF protein (p.Gly32_Ala33dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 33297573). ClinVar contains an entry for this variant (Variation ID: 41448). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Benign:1

Feb 08, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRAF c.95_100dupGCGCCG (p.Gly32_Ala33dup) results in an in-frame duplication that is predicted to duplicate two amino acids into the encoded protein. The variant allele was found at a frequency of 0.00017 in 157184 control chromosomes (gnomAD and publication data). The observed variant frequency is approximately 37 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRAF causing Cardiofaciocutaneous Syndrome phenotype (4.7e-06), strongly suggesting that the variant is benign. c.95_100dupGCGCCG has been reported in the literature in individuals affected with non-small cell lung cancer and hypertrophic cardiomyopathy as well as in one healthy individual (Shen_2019, Lin_2019, Micheu_2020). These reports do not provide unequivocal conclusions about association of the variant with Cardiofaciocutaneous Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

BRAF-related disorder Benign:1

Jun 23, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Noonan syndrome Benign:1

-

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Noonan syndrome and Noonan-related syndrome Benign:1

Nov 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397507458; hg19: chr7-140624403;