16-23635536-A-G

Variant names:

• chr16-23635536-A-G
• rs45494092
• NM_024675.4:c.1010T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_024675.4(PALB2):​c.1010T>C​(p.Leu337Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 1,613,480 control chromosomes in the GnomAD database, including 322 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. L337F) has been classified as Uncertain significance. The gene PALB2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.015 (37 hom., cov: 32)
  • Exomes 𝑓: 0.019 (285 hom.)
• Consequence: PALB2 NM_024675.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:28 O:1
• Conservation: PhyloP100: 0.842
• Publications: 58 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: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 25 uncertain in NM_024675.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0021042824).
• BP6: Variant 16-23635536-A-G is Benign according to our data. Variant chr16-23635536-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 126582.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0146 (2216/152220) while in subpopulation NFE AF = 0.0211 (1437/68006). AF 95% confidence interval is 0.0202. There are 37 homozygotes in GnomAd4. There are 1102 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 AR,AD gene

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.1010T>C	p.Leu337Ser	missense	Exon 4 of 13	NP_078951.2
	PALB2	NM_001407296.1		c.950T>C	p.Leu317Ser	missense	Exon 3 of 12	NP_001394225.1
	PALB2	NM_001407297.1		c.1010T>C	p.Leu337Ser	missense	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.1010T>C	p.Leu337Ser	missense	Exon 4 of 13	ENSP00000261584.4	Q86YC2
	PALB2	ENST00000568219.5	TSL:1	c.125T>C	p.Leu42Ser	missense	Exon 4 of 13	ENSP00000454703.2	H3BN63
	PALB2	ENST00000561514.3	TSL:5	c.1016T>C	p.Leu339Ser	missense	Exon 4 of 13	ENSP00000460666.3	A0AA52I2C1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2215 AN: 152102 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.00396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00950

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0399

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.0147 AC: 3679 AN: 250924 AF XY: 0.0143

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.00658

Gnomad ASJ exome AF: 0.00487

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0456

Gnomad NFE exome AF: 0.0192

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0191 AC: 27915 AN: 1461260 Hom.: 285 Cov.: 32 AF XY: 0.0186 AC XY: 13508 AN XY: 726942

African (AFR) AF: 0.00276 AC: 92 AN: 33378

American (AMR) AF: 0.00639 AC: 285 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00536 AC: 140 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00354 AC: 305 AN: 86198

European-Finnish (FIN) AF: 0.0448 AC: 2391 AN: 53384

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.0212 AC: 23614 AN: 1111766

Other (OTH) AF: 0.0178 AC: 1076 AN: 60346

GnomAD4 genome AF: 0.0146 AC: 2216 AN: 152220 Hom.: 37 Cov.: 32 AF XY: 0.0148 AC XY: 1102 AN XY: 74438

African (AFR) AF: 0.00395 AC: 164 AN: 41526

American (AMR) AF: 0.00949 AC: 145 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00353 AC: 17 AN: 4820

European-Finnish (FIN) AF: 0.0399 AC: 423 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0211 AC: 1437 AN: 68006

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.0162 Hom.: 92

Bravo AF: 0.0110

TwinsUK AF: 0.0259 AC: 96

ALSPAC AF: 0.0166 AC: 64

ESP6500AA AF: 0.00364 AC: 16

ESP6500EA AF: 0.0197 AC: 169

ExAC AF: 0.0142 AC: 1729

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0164

EpiControl AF: 0.0184

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (9)
-	-	7	Hereditary cancer-predisposing syndrome (7)
-	-	6	not provided (6)
-	1	4	Familial cancer of breast (5)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Fanconi anemia complementation group N (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.84
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.041
Sift	Benign	0.13	T
Sift4G	Uncertain	0.018	D
Polyphen		0.29	B
Vest4		0.065
MPC		0.077
ClinPred		0.0078	T
GERP RS		2.6
Varity_R		0.074
gMVP		0.25
Mutation Taster		=96/4	polymorphism (auto)

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: rs45494092; hg19: chr16-23646857; COSMIC: COSV55167558;