16-23621386-G-A

Variant names:

• chr16-23621386-G-A
• rs876660109
• NM_024675.4:c.3089C>T

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 1P and 2B. PM2_Supporting BP1 BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.3089C>T variant in PALB2 is a missense variant predicted to cause a substitution of threonine for isoleucine at amino acid 1030 (p.Thr1030Ile). This variant has been observed with another variant in PALB2 that is tentatively classified as likely pathogenic by HBOP VCEP in an individual without Fanconi Anemia (Ambry Genetics). The phase of the variants was not determined. This variant has been tested in multiple protein assays (PMID 33964450, 31636395, 31757951, 31586400); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. This variant is absent from gnomAD v2.1.1. 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 a variant of uncertain significance 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. (BS2_supporting, PM2_supporting, BP1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10579934/MONDO:0016419/020

• Frequency: Genomes: not found (cov: 32)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:5
• Conservation: PhyloP100: 6.04
• Publications: 17 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: ClinGen, Ambry Genetics
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• familial ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000261723 (HGNC:58305):

ACMG classification

Our verdict: Uncertain_significance. The variant received -1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	NM_024675.4	MANE Select	c.3089C>T	p.Thr1030Ile	missense	Exon 10 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.3029C>T	p.Thr1010Ile	missense	Exon 9 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.3017C>T	p.Thr1006Ile	missense	Exon 9 of 12	NP_001394226.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	ENST00000261584.9	TSL:1 MANE Select	c.3089C>T	p.Thr1030Ile	missense	Exon 10 of 13	ENSP00000261584.4
	PALB2	ENST00000568219.5	TSL:1	c.2204C>T	p.Thr735Ile	missense	Exon 10 of 13	ENSP00000454703.2
	PALB2	ENST00000561514.3	TSL:5	c.3095C>T	p.Thr1032Ile	missense	Exon 10 of 13	ENSP00000460666.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Familial cancer of breast (1)
-	1	-	Hereditary breast ovarian cancer syndrome (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)
-	1	-	PALB2-related cancer predisposition (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.51		Loss of sheet (P = 0.1158)
MVP		0.77
MPC		0.36
ClinPred		0.99	D
GERP RS		5.3
PromoterAI		-0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.68
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs876660109; hg19: chr16-23632707;