chr9-95150025-T-A

Variant names:

• chr9-95150025-T-A
• rs1800365
• NM_000136.3:c.584A>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000136.3(FANCC):​c.584A>T​(p.Asp195Val) variant causes a missense change. The variant allele was found at a frequency of 0.00394 in 1,614,040 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D195E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (25 hom.)
• Consequence: FANCC NM_000136.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:23 O:1
• Conservation: PhyloP100: 4.53
• Publications: 25 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]

AOPEP (HGNC:1361): (aminopeptidase O (putative)) This gene encodes a member of the M1 zinc aminopeptidase family. The encoded protein is a zinc-dependent metallopeptidase that catalyzes the removal of an amino acid from the amino terminus of a protein or peptide. This protein may play a role in the generation of angiotensin IV. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2010]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027212769).
• BP6: Variant 9-95150025-T-A is Benign according to our data. Variant chr9-95150025-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134305.
• BS2: High Homozygotes in GnomAdExome4 at 25 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000136.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCC	NM_000136.3	MANE Select	c.584A>T	p.Asp195Val	missense	Exon 7 of 15	NP_000127.2
	FANCC	NM_001243743.2		c.584A>T	p.Asp195Val	missense	Exon 7 of 15	NP_001230672.1
	FANCC	NM_001243744.2		c.584A>T	p.Asp195Val	missense	Exon 7 of 14	NP_001230673.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCC	ENST00000289081.8	TSL:1 MANE Select	c.584A>T	p.Asp195Val	missense	Exon 7 of 15	ENSP00000289081.3
	FANCC	ENST00000375305.6	TSL:1	c.584A>T	p.Asp195Val	missense	Exon 7 of 15	ENSP00000364454.1
	FANCC	ENST00000490972.7	TSL:1	c.584A>T	p.Asp195Val	missense	Exon 7 of 14	ENSP00000479931.1

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 435 AN: 152064 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00469

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00313 AC: 787 AN: 251330 AF XY: 0.00319

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00464

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00406 AC: 5932 AN: 1461858 Hom.: 25 Cov.: 31 AF XY: 0.00413 AC XY: 3002 AN XY: 727222

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.00280 AC: 125 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00314 AC: 82 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00344 AC: 297 AN: 86246

European-Finnish (FIN) AF: 0.000543 AC: 29 AN: 53416

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5766

European-Non Finnish (NFE) AF: 0.00453 AC: 5036 AN: 1112000

Other (OTH) AF: 0.00508 AC: 307 AN: 60396

GnomAD4 genome AF: 0.00286 AC: 435 AN: 152182 Hom.: 1 Cov.: 32 AF XY: 0.00263 AC XY: 196 AN XY: 74394

African (AFR) AF: 0.000626 AC: 26 AN: 41522

American (AMR) AF: 0.00321 AC: 49 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00229 AC: 11 AN: 4812

European-Finnish (FIN) AF: 0.000755 AC: 8 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00469 AC: 319 AN: 68010

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00454 Hom.: 1

Bravo AF: 0.00317

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00305 AC: 370

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00486

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:23 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:8 Other:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

Aug 24, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 29, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 17, 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.

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband of European ancestry in homozygous state (Verlander 1994). Classified as Benign in ClinVar by GeneDx. MAF 0.4%.

May 21, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 01, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

not provided Uncertain:1 Benign:4

Feb 28, 2020

Leiden Open Variation Database

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: curation

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

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 26, 2015

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FANCC: BP4, BS2

Fanconi anemia complementation group C Uncertain:1 Benign:4

May 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

May 18, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 25, 2017

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

May 29, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

Fanconi anemia Benign:3

Oct 16, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 14, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:2

Sep 21, 2018

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.

Dec 03, 2015

Vantari Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fanconi anemia complementation group A Benign:1

May 28, 2019

Mendelics

Significance: Likely 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: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FANCC p.Asp195Val variant was identified in 2 of 436 proband chromosomes (frequency: 0.005) from individuals or families of northern or eastern European and southern Italian descent with pancreatic cancer and Fanconi Anemia (Verlander 1994, Van Der Heijden 2003). The variant was also identified in the following databases: dbSNP (ID: rs1800365), in the ClinVar database as benign by GeneDx, Emory Genetics, Invitae, Vantari Genetics; as likely benign by Centre for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, Prevention Genetics and Laboratory for Molecular Medicine, Partners Health Care Personalized Medicine; and as uncertain significance by Division of Genomic Diagnostics, Children's Hospital of Philadelphia Study Description: and in Clinvitae database as benign by Emyclass. The variant was also listed in the LOVD 3.0 database; however no relevant information was given. The variant was not identified in Cosmic and MutDB. In addition, the variant was identified in the 1000 Genomes Project in 13 of 5000 chromosomes (frequency: 0.003) and the NHLBI GO Exome Sequencing Project in 40 of 8600 European American and in 4 of 4406 African American alleles. The variant was identified in control databases in 842 (4 homozygous) of 277070 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017). Breakdown of observations by population is: European (Non-Finnish) in 568 (3 homozygous) of 126606 chromosomes (freq: 0.004), Ashkenazi Jewish in 36 of 10144 chromosomes (freq: 0.004), South Asian in 107 of 30766 chromosomes (freq: 0.003), Latino in 95 (1 homozygous) of 34412 chromosomes (freq: 0.003), Other in 16 of 6456 chromosomes (freq: 0.001), African in 12 of 24028 chromosomes (freq: 0.0005), and European (Finnish) in 8 of 25788 chromosomes (freq: 0.0003), while not observed in the East Asian population. The p.Asp195 residue is conserved in in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Asp195Val variant may impact the protein; however, this information is not predictive enough to assume 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. The variant is located with the Fanconi anaemia group C protein functional domain. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we lean towards a more benign role for this variant. This variant is classified as likely benign.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.5
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.83
MVP		0.87
MPC		0.40
ClinPred		0.028	T
GERP RS		4.8
Varity_R		0.45
gMVP		0.49
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1800365; hg19: chr9-97912307;