rs1800365

chr9-95150025-T-Achr9-95150025-T-C

Variant summary

Our verdict is Benign. Variant got -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:22 O:1
• Conservation: PhyloP100: 4.53

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

Verdict is Benign. Variant got -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 id is 134305.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Benign=8, Uncertain_significance=3, not_provided=1}. Variant chr9-95150025-T-A is described in Lovd as [Likely_benign]. Variant chr9-95150025-T-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCC	NM_000136.3	c.584A>T	p.Asp195Val	missense_variant	7/15	ENST00000289081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCC	ENST00000289081.8	c.584A>T	p.Asp195Val	missense_variant	7/15	1	NM_000136.3	P1

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

GnomAD3 exomes AF: 0.00313 AC: 787 AN: 251330 Hom.: 4 AF XY: 0.00319 AC XY: 433 AN XY: 135826

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 SAS exome AF: 0.00333

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

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00280

Gnomad4 ASJ exome AF: 0.00314

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00344

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.00453

Gnomad4 OTH exome AF: 0.00508

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

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00321

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00229

Gnomad4 FIN AF: 0.000755

Gnomad4 NFE AF: 0.00469

Gnomad4 OTH AF: 0.00378

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:22 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:8 Other:1

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 21, 2021	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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%. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 29, 2015	- -
Uncertain significance, flagged submission	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Uncertain:1 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 26, 2015	- -
Uncertain significance, flagged submission	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	FANCC: BP4, BS2 -

Fanconi anemia complementation group C Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 29, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	May 25, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

Fanconi anemia Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 14, 2017	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Dec 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 21, 2018	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. -

Fanconi anemia complementation group A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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 v4.3

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;D;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.87	D
MetaRNN	Benign	0.027	T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.4	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-5.6	D;D;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0040	D;D;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.99	D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1800365; hg19: chr9-97912307; COSMIC: COSV100002740;