rs147045425

Variant names:

• chr16-23607965-C-G
• rs147045425
• NM_024675.4:c.3249G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-23607965-C-G
• chr16-23607965-C-T
• chr16-23607965-C-A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.3249G>C (p.Glu1083Asp) variant in PALB2 is a missense variant predicted to cause substitution of glutamic acid by aspartic acid at amino acid 1083 (p.Glu1083Asp). This variant has a gnomAD v2.1.1 filtering allele frequency of 0.001331 in the Latino/Admixed American population, which is higher than the HBOP VCEP threshold (>0.001) for BA1, and therefore meets this criterion. This variant is functional in multiple protein assays; however, due to a lack of positive missense controls with known clinical impact, these assays do not meet the requirements for use by the HBOP VCEP (PMID:31636395). PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BA1, BP1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA288472/MONDO:0016419/020

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Benign reviewed by expert panel U:4 B:11
• Conservation: PhyloP100: 1.40
• Publications: 8 publications found

Genes affected

PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]

PALB2 Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• PALB2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Fanconi anemia complementation group N

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• pancreatic cancer, susceptibility to, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PALB2-AS1 (HGNC:58305):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024675.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	NM_024675.4	MANE Select	c.3249G>C	p.Glu1083Asp	missense	Exon 12 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.3189G>C	p.Glu1063Asp	missense	Exon 11 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.3177G>C	p.Glu1059Asp	missense	Exon 11 of 12	NP_001394226.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.3249G>C	p.Glu1083Asp	missense	Exon 12 of 13	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.2364G>C	p.Glu788Asp	missense	Exon 12 of 13	ENSP00000454703.2	H3BN63
	PALB2	ENST00000561514.3	TSL:5	c.3255G>C	p.Glu1085Asp	missense	Exon 12 of 13	ENSP00000460666.3	A0AA52I2C1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000243 AC: 61 AN: 251476 AF XY: 0.000169

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000540 AC: 79 AN: 1461850 Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00141 AC: 63 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74298

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.000196 AC: 3 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.000162

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000173 AC: 21

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	3	2	Familial cancer of breast (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	1	-	Anaplastic ependymoma (1)
-	-	1	not specified (1)
-	-	1	PALB2-related cancer predisposition (1)
-	-	1	PALB2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.4
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.081
Sift	Uncertain	0.023	D
Sift4G	Benign	0.062	T
Polyphen		0.97	D
Vest4		0.44
MutPred		0.10		Loss of methylation at K1080 (P = 0.0556)
MVP		0.51
MPC		0.067
ClinPred		0.15	T
GERP RS		3.8
Varity_R		0.15
gMVP		0.23
Mutation Taster		=92/8	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: rs147045425; hg19: chr16-23619286; COSMIC: COSV55168291;