9-95172077-C-T

Variant names:

• chr9-95172077-C-T
• rs1800362
• NM_000136.3:c.416G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000136.3(FANCC):​c.416G>A​(p.Gly139Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,612,860 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G139R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (37 hom.)
• Consequence: FANCC NM_000136.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:15 O:1
• Conservation: PhyloP100: 3.06
• Publications: 12 publications found

Genes affected

FANCC (HGNC:3584): (FA complementation group C) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group C. [provided by RefSeq, Jul 2008]

FANCC Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• colorectal cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• malignant pancreatic neoplasm

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009651393).
• BP6: Variant 9-95172077-C-T is Benign according to our data. Variant chr9-95172077-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0136 (2064/152124) while in subpopulation AFR AF = 0.0464 (1922/41466). AF 95% confidence interval is 0.0446. There are 41 homozygotes in GnomAd4. There are 969 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCC	NM_000136.3	c.416G>A	p.Gly139Glu	missense_variant	Exon 5 of 15	ENST00000289081.8	NP_000127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCC	ENST00000289081.8	c.416G>A	p.Gly139Glu	missense_variant	Exon 5 of 15	1	NM_000136.3	ENSP00000289081.3

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2061 AN: 152006 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0464

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00629

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00348 AC: 873 AN: 251150 AF XY: 0.00262

Gnomad AFR exome AF: 0.0468

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00141 AC: 2060 AN: 1460736 Hom.: 37 Cov.: 29 AF XY: 0.00124 AC XY: 902 AN XY: 726760

African (AFR) AF: 0.0480 AC: 1604 AN: 33398

American (AMR) AF: 0.00291 AC: 130 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86226

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53410

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5758

European-Non Finnish (NFE) AF: 0.0000900 AC: 100 AN: 1111160

Other (OTH) AF: 0.00315 AC: 190 AN: 60336

GnomAD4 genome AF: 0.0136 AC: 2064 AN: 152124 Hom.: 41 Cov.: 32 AF XY: 0.0130 AC XY: 969 AN XY: 74370

African (AFR) AF: 0.0464 AC: 1922 AN: 41466

American (AMR) AF: 0.00628 AC: 96 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68006

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.00538 Hom.: 57

Bravo AF: 0.0153

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0449 AC: 198

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00422 AC: 513

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:4

Apr 29, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.416G>A variant affects a conserved nucleotide, resulting in amino acid change from Gly to Glu. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is found in 508/120796 control chromosomes (6 homozygotes) at a frequency of 0.0042054. The variant was present predominantly in the African population at a frequency of 4.5% which is about 26 times of the maximal expected frequency of a pathogenic allele (0.0017678), strongli indicating this variant is benign. In addition, publications/clinical laboratories have classified this variant as benign. Taken together, this variant was classified as benign. -

Feb 28, 2020

Leiden Open Variation Database

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -

Sep 20, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:4 Other:1

Jun 23, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: 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. -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2017

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Fanconi anemia complementation group C Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group A Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FANCC p.Gly139Glu variant was identified in 5 of 1190 proband chromosomes (frequency: 0.0042) from individuals or families with Fanconi anemia and pancreatic cancer, and was present in 1 of 1362 control chromosomes (frequency: 0.00073) from healthy individuals (Couch_2005_15695377, Verlander_1994_8128956). The variant was also identified in dbSNP (ID: rs1800362) as “With other allele,” ClinVar (as benign by GeneDx, Invitae, PreventionGenetics, Ambry Genetics, and Laboratory Corporation of America, and as likely benign by Illumina and Center for Pediatric Genomic Medicine Children's Mercy Hospital), and Clinvitae (as in ClinVar) databases. The variant was not identified in Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 1253 of 276924 chromosomes (30 homozygous) at a frequency of 0.004525 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1133 of 24008 chromosomes (freq: 0.04719), Other in 13 of 6454 chromosomes (freq: 0.002014), Latino in 82 of 34404 chromosomes (freq: 0.002383), European (Non-Finnish) in 14 of 126516 chromosomes (freq: 0.000111), and South Asian in 11 of 30768 chromosomes (freq: 0.000358), while the variant was not observed in the Ashkenazi Jewish, East Asian, or European Finnis populations. The p.Gly139Glu residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Hereditary cancer-predisposing syndrome Benign:1

Aug 18, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;T;.;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.73	.;T;T;T;T
MetaRNN	Benign	0.0097	T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.4	M;M;.;.;.
PhyloP100		3.1
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.8	D;D;.;.;D
REVEL	Benign	0.27
Sift	Uncertain	0.0020	D;D;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;.;D
Polyphen		1.0	D;D;.;.;D
Vest4		0.56
MVP		0.92
MPC		0.19
ClinPred		0.024	T
GERP RS		5.3
Varity_R		0.72
gMVP		0.72
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1800362; hg19: chr9-97934359; COSMIC: COSV99057233;