rs749443090

Variant names:

• chr16-23637855-T-A
• rs749443090
• NM_024675.4:c.206A>T

Your query was ambiguous. Multiple possible variants found:

• chr16-23637855-T-A
• chr16-23637855-T-C
• chr16-23637855-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024675.4(PALB2):​c.206A>T​(p.His69Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H69Y) has been classified as Likely benign. The gene PALB2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: -0.400
• Publications: 2 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

Specifications for PALB2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25965077).

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.206A>T	p.His69Leu	missense	Exon 3 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.146A>T	p.His49Leu	missense	Exon 2 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.206A>T	p.His69Leu	missense	Exon 3 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.206A>T	p.His69Leu	missense	Exon 3 of 13	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.-680A>T		5_prime_UTR	Exon 3 of 13	ENSP00000454703.2	H3BN63
	PALB2	ENST00000561514.3	TSL:5	c.212A>T	p.His71Leu	missense	Exon 3 of 13	ENSP00000460666.3	A0AA52I2C1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	Hereditary cancer-predisposing syndrome (3)
-	1	1	Familial cancer of breast (2)
-	2	-	not provided (2)
-	1	-	Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3;C5830615:Breast-ovarian cancer, familial, susceptibility to, 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	7.1
DANN	Benign	0.96
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.0023
Eigen_PC	Benign	-0.089
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-0.40
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.082
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.018	D
Polyphen		0.94	P
Vest4		0.25
MutPred		0.22		Loss of methylation at K68 (P = 0.0779)
MVP		0.72
MPC		0.15
ClinPred		0.68	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.051

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: rs749443090; hg19: chr16-23649176;