16-23629706-G-C

Variant names:

• chr16-23629706-G-C
• rs876659879
• NM_024675.4:c.2448C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BP6

The NM_024675.4(PALB2):​c.2448C>G​(p.Phe816Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F816Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.739
• Publications: 3 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• 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: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 38 uncertain in NM_024675.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05322081).
• BP6: Variant 16-23629706-G-C is Benign according to our data. Variant chr16-23629706-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 232620.

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.2448C>G	p.Phe816Leu	missense	Exon 5 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.2388C>G	p.Phe796Leu	missense	Exon 4 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.2448C>G	p.Phe816Leu	missense	Exon 5 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.2448C>G	p.Phe816Leu	missense	Exon 5 of 13	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.1563C>G	p.Phe521Leu	missense	Exon 5 of 13	ENSP00000454703.2	H3BN63
	PALB2	ENST00000561514.3	TSL:5	c.2454C>G	p.Phe818Leu	missense	Exon 5 of 13	ENSP00000460666.3	A0AA52I2C1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727248

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

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: 0.00000180 AC: 2 AN: 1112010

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Familial cancer of breast (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.8
DANN	Benign	0.74
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.74
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.062
Sift	Benign	0.55	T
Sift4G	Benign	0.56	T
Polyphen		0.0020	B
Vest4		0.10
MutPred		0.12		Gain of glycosylation at S815 (P = 0.1129)
MVP		0.17
MPC		0.059
ClinPred		0.028	T
GERP RS		2.0
Varity_R		0.057
gMVP		0.11
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: rs876659879; hg19: chr16-23641027;