16-23603502-G-T

Variant names:

• chr16-23603502-G-T
• rs146659762
• NM_024675.4:c.3518C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_024675.4(PALB2):​c.3518C>A​(p.Ala1173Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1173T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.59
• Publications: 5 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 34 uncertain in NM_024675.4
• PM2: Very rare variant in population databases, with high coverage

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.3518C>A	p.Ala1173Asp	missense	Exon 13 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.3458C>A	p.Ala1153Asp	missense	Exon 12 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.3446C>A	p.Ala1149Asp	missense	Exon 12 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.3518C>A	p.Ala1173Asp	missense	Exon 13 of 13	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.2633C>A	p.Ala878Asp	missense	Exon 13 of 13	ENSP00000454703.2	H3BN63
	PALB2	ENST00000561514.3	TSL:5	c.3524C>A	p.Ala1175Asp	missense	Exon 13 of 13	ENSP00000460666.3	A0AA52I2C1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Familial cancer of breast (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.26
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.36		Gain of relative solvent accessibility (P = 0.0215)
MVP		0.73
MPC		0.41
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.94
gMVP		0.79

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: rs146659762; hg19: chr16-23614823;