NM_024675.4:c.2737C>T

Variant names:

• chr16-23626247-G-A
• rs1555459923
• NM_024675.4:c.2737C>T

Variant summary

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

The NM_024675.4(PALB2):​c.2737C>T​(p.His913Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. H913L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.09
• Publications: 1 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALB2	NM_024675.4	MANE Select	c.2737C>T	p.His913Tyr	missense	Exon 7 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.2677C>T	p.His893Tyr	missense	Exon 6 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.2665C>T	p.His889Tyr	missense	Exon 6 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.2737C>T	p.His913Tyr	missense	Exon 7 of 13	ENSP00000261584.4
	PALB2	ENST00000568219.5	TSL:1	c.1852C>T	p.His618Tyr	missense	Exon 7 of 13	ENSP00000454703.2
	PALB2	ENST00000561514.3	TSL:5	c.2743C>T	p.His915Tyr	missense	Exon 7 of 13	ENSP00000460666.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.050	T
Eigen	Benign	0.10
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.13
Sift	Benign	0.22	T
Sift4G	Uncertain	0.031	D
Polyphen		0.93	P
Vest4		0.66
MutPred		0.40		Gain of sheet (P = 0.039)
MVP		0.49
MPC		0.36
ClinPred		0.88	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555459923; hg19: chr16-23637568;