rs1555461877

Variant names:

• chr16-23636334-T-A
• rs1555461877
• NM_024675.4:c.212A>T

Your query was ambiguous. Multiple possible variants found:

• chr16-23636334-T-A
• chr16-23636334-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024675.4(PALB2):​c.212A>T​(p.Glu71Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E71G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PALB2 NM_024675.4 missense, splice_region
• Scores: Splicing: ADA: 0.003677
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• 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: 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4012837).

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.212A>T	p.Glu71Val	missense splice_region	Exon 4 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.152A>T	p.Glu51Val	missense splice_region	Exon 3 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.212A>T	p.Glu71Val	missense splice_region	Exon 4 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.212A>T	p.Glu71Val	missense splice_region	Exon 4 of 13	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.-674A>T		splice_region	Exon 4 of 13	ENSP00000454703.2	H3BN63
	PALB2	ENST00000568219.5	TSL:1	c.-674A>T		5_prime_UTR	Exon 4 of 13	ENSP00000454703.2	H3BN63

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1439388 Hom.: 0 Cov.: 29 AF XY: 0.00000140 AC XY: 1 AN XY: 715276

African (AFR) AF: 0.00 AC: 0 AN: 32788

American (AMR) AF: 0.00 AC: 0 AN: 42442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25762

East Asian (EAS) AF: 0.00 AC: 0 AN: 39074

South Asian (SAS) AF: 0.00 AC: 0 AN: 82380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1099390

Other (OTH) AF: 0.00 AC: 0 AN: 59422

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	0.0089	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.0
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.11
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.42
MutPred		0.18		Loss of ubiquitination at K68 (P = 0.022)
MVP		0.80
MPC		0.29
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.39
gMVP		0.12
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0037
dbscSNV1_RF	Benign	0.13
SpliceAI score (max)		0.040		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: rs1555461877; hg19: chr16-23647655;